Compositions for detecting complement factor H (CFH) and complement factor I (CFI) polymorphisms

ABSTRACT

The invention provides methods and compositions for treating various degenerative diseases (e.g., AMD) with a factor D inhibitor (e.g., anti-factor D antibody or antigen-binding fragment thereof). Also provided are methods of selecting or identifying patients for treatment with a factor D inhibitor. Methods include the use of prognostic and/or predictive biomarkers.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication Nos. 61/864,941, filed on Aug. 12, 2013, and 61/866,651,filed on Aug. 16, 2013, and 61/872,098, filed on Aug. 30, 2013, and61/988,012, filed on May 2, 2014, and 62/021,487, filed on Jul. 7, 2014,the contects of the foregoing applications are incorporated herein byreference in their entirety.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Aug. 11, 2014, isnamed P5661R1-US_SL.txt and is 19,281 bytes in size.

FIELD OF THE INVENTION

The invention involves methods and compositions for treating variouscomplement-associated conditions (e.g., age-related maculardegeneration) with a factor D inhibitor (e.g., an anti-factor D antibodyor antigen-binding fragment thereof). Also provided are methods ofselecting or identifying patients for treatment with a factor Dinhibitor. Methods include the use of prognostic and/or predictivebiomarkers.

BACKGROUND

The complement system plays a central role in the clearance of immunecomplexes and the immune response to infectious agents, foreignantigens, virus-infected cells and tumor cells. However, complement isalso involved in pathological inflammation and in autoimmune diseases.Therefore, inhibition of excessive or uncontrolled activation of thecomplement cascade could provide clinical benefit to patients with suchdiseases and conditions.

The complement system encompasses two distinct activation pathways,designated the classical and the alternative pathways (V. M. Holers, InClinical Immunology: Principles and Practice, ed. R. R. Rich, MosbyPress; 1996, 363-391). The classical pathway is acalcium/magnesium-dependent cascade which is normally activated by theformation of antigen-antibody complexes. The alternative pathway is amagnesium-dependent cascade which is activated by deposition andactivation of C3 on certain susceptible surfaces (e.g. cell wallpolysaccharides of yeast and bacteria, and certain biopolymermaterials). Activation of the complement pathway generates biologicallyactive fragments of complement proteins, e.g. C3a, C4a and C5aanaphylatoxins and C5b-9 membrane attack complexes (MAC), which mediateinflammatory activities involving leukocyte chemotaxis, activation ofmacrophages, neutrophils, platelets, mast cells and endothelial cells,vascular permeability, cytolysis, and tissue injury.

Factor D is a highly specific serine protease essential for activationof the alternative complement pathway. It cleaves factor B bound to C3b,generating the C3b/Bb enzyme which is the active component of thealternative pathway C3/C5 convertases. Factor D may be a suitable targetfor inhibition, since its plasma concentration in humans is very low(1.8 μg/ml), and it has been shown to be the limiting enzyme foractivation of the alternative complement pathway (P. H. Lesavre and H.J. Müller-Eberhard. J. Exp. Med., 1978; 148: 1498-1510; J. E. Volanakiset al., New Eng. J. Med., 1985; 312: 395-401).

The down-regulation of complement activation has been demonstrated to beeffective in treating several disease indications in animal models andin ex vivo studies, e.g. systemic lupus erythematosus andglomerulonephritis (Y. Wang et al., Proc. Natl. Acad. Sci.; 1996, 93:8563-8568), rheumatoid arthritis (Y. Wang et al., Proc. Natl. Acad.Sci., 1995; 92: 8955-8959), cardiopulmonary bypass and hemodialysis (C.S. Rinder, J. Clin. Invest., 1995; 96: 1564-1572), hyperacute rejectionin organ transplantation (T. J. Kroshus et al., Transplantation, 1995;60: 1194-1202), myocardial infarction (J. W. Homeister et al., J.Immunol., 1993; 150: 1055-1064; H. F. Weisman et al., Science, 1990;249: 146-151), reperfusion injury (E. A. Amsterdam et al., Am. J.Physiol., 1995; 268: H448-H457), and adult respiratory distress syndrome(R. Rabinovici et al., J. Immunol., 1992; 149: 1744-1750). In addition,other inflammatory conditions and autoimmune/immune complex diseases arealso closely associated with complement activation (V. M. Holers, ibid.,B. P. Morgan. Eur. J. Clin. Invest., 1994:24:219-228), including thermalinjury, severe asthma, anaphylactic shock, bowel inflammation,urticaria, angioedema, vasculitis, multiple sclerosis, myastheniagravis, membranoproliferative glomerulonephritis, and Sjögren'ssyndrome.

Age-related macular degeneration (AMD), when left untreated, is theleading cause of irreversible blindness in people 50 years of age orolder in the developed world (Friedman et al., Arch Opthalmol,122:564-72 (2004)). Approximately 8 million Americans have anintermediate stage of AMD (characterized by the presence of large-sizeddrusen in the macula (center of the retina)), placing them at risk fordeveloping advanced disease and vision loss. Advanced AMD is classifiedinto two clinical forms: geographic atrophy (GA) and an exudative or wetform characterized by choroidal neovascularization (CNV) (Age-RelatedEye Disease Study [AREDS] Research Group, Arch Ophthalmol, 121:1621-24(2003)). GA refers to confluent areas of retinal pigment epithelial(RPE) cell death accompanied by overlying photoreceptor atrophy. GA hasa substantial impact on visual function: approximately 40% of a subsetof patients has been shown to lose at least 3 Snellen equivalent linesof vision over 2 years (Sunness et al., Retina, 7:204-10 (2007)).Although the etiology of AMD is largely unknown, age, smoking ethnicity,diet and genetics have been suggested to be risk factors in AMD (Amabtiet al., Surv Opthalmol, 48(3): 257-93 (2003); Gorin et al., Mol AspectsMed, 33:467-486 (2012)) and the alternative complement pathway (ACP)have been implicated in AMD (de Jong, N. Engl J. Med., 355: 1474-1485(2006)). Increased activation of ACP has been found in drusen,lipoproteinous depositions in the space between the RPE and Bruch'smembrane, which are a hallmark of AMD. Moreover, a role for ACPactivation in AMD has been supported by human genetics (Yates et al.,New Engl J Med, 357: 553-61 (2007)). Complement factor D is arate-limiting enzyme that plays a pivotal role in the activation of thealternative complement pathway (ACP). Evidence for factor D in thepathogenesis of AMD includes protection against oxidativestress-mediated photoreceptor degeneration in a murine model withgenetic deficiency of factor D (Rohrer et al., Invest Ophtalmol Vis Sci,48:5282-89 (2007)) and detection of increased systemic activation ofcomplement, including factor D, in the serum of AMD patients versuscontrols, suggesting that AMD may be a systemic disease with localmanifestations in the aging macula (Scholl et al., PLos ONE, 3(7):e2593(2008)). Moreover, multiple papers on the genetics of AMD haveindependently confirmed a single nucleotide polymorphism in complementfactor H(CFH). Y402H that was strongly linked to increased risk ofdeveloping both early and late AMD (Edwards et al., Science, 308(5720):421-4 (2005); Hageman et al., PNAS, 102(20): 7227-32 (2005); Haines etal., Science, 208(5720): 419-21 (2005); Klein et al., Science,308(5720): 385-9 (2005); Prosser et al., J. Exp. Med., 204(10: 2277-83(2007); Zareparsi et al., Am J. Hum Genet, 77:149-153 (2005)). Otherrisk alleles include polymorphisms in a complement factor H(CFH) risklocus (rs10737680), in a complement factor I (CFI) risk locus(rs4698775), in a complement component 2/complement factor B (C2/CFB)risk locus (rs429608), and in a complement component (C3) risk locus(rs2230199) (Fritsche et al., Nat Genet, 45:433-439 (2013)). CFI, CFH,C2, CFB and C3 are additional members of the complement pathway.Additional SNPs associated with genes in the complement pathway andtheir correlation with AMD have been implicated in, e.g., PCTpublications WO2011/017229, WO2009/146204 and WO2009/134709. None ofthese references, however, disclosed or suggested correlation of theidentified SNPs with how the patient's disease progresses over time orhow well the patient responds to AMD therapy. In a prospective study ofgenetic effects on AMD progression, genetic variants such as SNPs in thecomplement pathway were associated with progression from intermediatedrusen to large drusen and from large drusen to GA or NY. Yu et al.,Invest. Ophthalm. & Visual Sci., 53:1548-56 (2012). The results suggestthat genes associated with AMD may be involved in transitions betweendistinctly different AMD stages during progression. It was not known,however, whether the identified genes are associated with rate ofdisease progression, e.g., within an advanced stage such as GA.

Currently, anti-VEGF (vascular endothelial growth factor) is thestandard of care for treatment of most cases of the wet from of advancedAMD. There is currently no effective treatment that halts or slows theprogression of GA. There is no approved treatment to prevent progressionof GA, creating a significant unmet need for patients with GA. Thus,there is a need to identify efficacious therapies for GA and improvedmethods for understanding how to treat GA patients. Specifically,diagnostic methods useful for identifying patients at risk for increasedGA progression rate and likely to benefit from anti-factor D antibodytreatment would greatly benefit clinical management of these patients.This invention meets these and other needs.

All references cited herein, including patent applications andpublications, are incorporated by reference in their entirety for anypurpose.

SUMMARY OF THE INVENTION

The present invention is based in part on the novel and surprisingfindings collected from a clinical trial that certain polymorphismsrelated to genes in the complement pathway are reliable predictors forAMD patients' progression rate as well as their response to ananti-Factor D therapy. Methods of treatment, diagnosis/prognosis andpredicting response to treatment as provided herein can be applied topatients suffering from age-related macular degeneration.

One embodiment of the invention provides methods of identifying anindividual who has an increased risk for progression of AMD (e.g.intermediate or advanced AMD such as wet (neovascular/exudative) AMD orgeographic atrophy), the method comprising determining the genotype ofan individual, wherein an individual who is determined to carry a riskallele (e.g. a degenerative disease-associated polymorphisms such as anAMD-associated polymorphism) is identified as an individual with anincreased risk of progression of AMD (e.g. intermediate or advanced AMDsuch as wet (neovascular/exudative) AMD or geographic atrophy). In someembodiments, increased risk of progression of AMD includes progressionfrom early to intermediate AMD and/or intermediate to advanced AMD. Insome embodiments, the risk allele is the minor allele of a selected SNP.In some embodiments, the risk allele is the major allele of a selectedSNP. In some embodiments, increased risk of progression of AMD includesprogression from early to more advanced disease in each of the AMDstages (includes early AMD, intermediate AMD and advanced AMD) whereinearly AMD is characterized by multiple small (<63 μm), or ≥1intermediate drusen (≥63 μm and <125 μm); intermediate AMD ischaracterized by many intermediate or ≥1 large drusen (≥125 μm) oftenaccompanied by hyper- or hypopigmentation of the retinal pigmentepithelium; and advanced AMD is characterized by geographic atrophy (GA)or neovascular (wet) AMD). In some embodiments, the risk allele may be acomplement factor I (CFI) risk allele, a complement factor H(CFH) riskallele, a complement component 2 (C2) risk allele, a complement factor B(CFB) risk allele and/or a complement component 3 (C3) risk allele. Insome embodiments, the CFI risk allele is the rs4698775:G allele, orequivalent allele thereof, or comprises a G at the selected SNPrs4698775, or an alternate SNP in linkage disequilibrium to rs4698775.In some embodiments, the CFI risk allele is the rs17440077 G: allele, orequivalent allele thereof, or comprises a G at the selected SNPrs17440077, or an alternate SNP in linkage disequilibrium to rs17440077.In some embodiments, the CFH risk allele is the rs10737680:A allele, orequivalent allele thereof, or comprises an A at the SNP rs10737680, oran alternate SNP in linkage disequilibrium to rs10737680. In someembodiments, the CFH risk allele is the rs1329428:G allele, orequivalent allele thereof, or comprises a G at the SNP rs1329428, or analternate SNP in linkage disequilibrium to rs1329428. In someembodiments, the C2 risk allele is the rs429608:G allele, or equivalentallele thereof, or comprises a G at the SNP rs429608 or an alternate SNPin linkage disequilibrium to rs429608. In some embodiments, the CFB riskallele is the rs429608:G allele, or equivalent allele thereof, orcomprises a G at SNP rs429608 or an alternate SNP in linkagedisequilibrium to rs429608. In some embodiments, the C3 risk allele isthe rs2230199:G allele, or equivalent allele thereof, or comprises a Gat the SNP rs2230199 or an alternate SNP in linkage disequilibrium tors2230199. In some embodiments, the linkage disequilibrium is a D′measure or an r² measure. In some embodiments, the D′ measure betweenthe selected SNP and the alternate SNP is ≥0.60. In some embodiments,the D′ measure between the selected SNP and the alternate SNP is ≥0.70,0.80 or 0.90. In some embodiments, the D′ measure between the selectedSNP and the alternate SNP is 1.0. In some embodiments, the r² measurebetween the selected SNP and the alternate SNP is ≥0.60. In someembodiments the r² measure between the selected SNP and the alternateSNP is ≥0.70, 0.80 or 0.90. In some embodiments, the r² measure betweenthe selected SNP and the alternate SNP is 1.0. In some embodiments, thealternate SNP is a SNP designated in Tables 4-7. In some embodiments,the SNP rs4698775 is located at position 110590479 on human chromosome 4(Genome Reference Consortium GRCh37; UCSC Genome HG19 Assembly; February2009). The G allele changes the nucleotide sequence from T to G. In someembodiments, the SNP rs17440077 is located at position 110537567 onhuman chromosome 4 (Genome Reference Consortium GRCh37; UCSC Genome HG19Assembly; February 2009). The G allele changes the nucleotide sequencefrom A to G. In some embodiments, the SNP rs10737680 is located atposition 196679455 on human chromosome 1 (Genome Reference ConsortiumGRCh37; UCSC Genome HG19 Assembly; February 2009). The A allele changesthe nucleotide sequence form C to A. In some embodiments, the SNPrs1329428 is located at position 196702810 on human chromosome 1 (GenomeReference Consortium GRCh37; UCSC Genome HG19 Assembly; February 2009).The G allele changes the nucleotide sequence from A to G. In someembodiments, the SNP rs429608 is located at position 31930462 on humanchromosome 6 (Genome Reference Consortium GRCh37; UCSC Genome HG19Assembly; February 2009). The G allele changes the nucleotide sequencefrom A to G. In some embodiments, the SNP rs2230199 is located atposition 6718387 on human chromosome 19 (Genome Reference ConsortiumGRCh37; UCSC Genome HG19 Assembly; February 2009). The G allele changesthe nucleotide sequence from C to G and the encoded amino acid from anarginine to glycine. In some embodiments, the alternate SNP is locatedon human chromosome 4 between SEC24B gene and EGF gene (for rs4698775)(Genome Reference Consortium GRCh37; UCSC Genome HG19 Assembly; February2009), human chromosome 4 between SEC24B gene and EGF gene (GenomeReference Consortium GRCh37; UCSC Genome HG19 Assembly; February 2009)(for rs17440077), human chromosome 1 between KCNT2 gene and LHX9 gene(Genome Reference Consortium GRCh37; UCSC Genome HG19 Assembly; February2009) (for rs10737680), human chromosome 1 between KCNT2 gene and LHX9gene (Genome Reference Consortium GRCh37; UCSC Genome HG19 Assembly;February 2009) (for rs1329428), human chromosome 6 between SLC44A4 geneand TNXB gene (Genome Reference Consortium GRCh37; UCSC Genome HG19Assembly; February 2009) (for rs429608), human chromosome 19 betweenTNFSF14 gene and VAV1 gene (Genome Reference Consortium GRCh37; UCSCGenome HG19 Assembly; February 2009) (for rs2230199). In someembodiments, the alternate SNP is located within 500,000 base pairsupstream or downstream of the selected SNP In some embodiments, thepatient is determined to carry a CFI risk allele and/or a CFH riskallele and/or a C2 risk allele and/or a CFB risk allele and/or a C3 riskallele. In some embodiments, the individual is determined to carry 1, 2,3, 4, 5, 6, 7, 8, 9, 10, etc. AMD risk alleles. In some embodiments,presence of a risk allele in an individual comprises determining theidentity of the nucleotide at the polymorphism from nucleic acidprovided from a sample from an individual. In some embodiments, thenucleic acid sample comprises DNA. In some embodiments, the nucleic acidsample comprises RNA. In some embodiments, the nucleic acid sample isamplified. In some embodiments, the nucleic acid sample is amplified bya polymerase chain reaction. In some embodiments, the polymorphism isdetected by polymerase chain reaction or sequencing. In someembodiments, the polymorphism is detected by amplification of a targetregion containing at least one polymorphism, and hybridization with atleast one sequence-specific oligonucleotide that hybridizes understringent conditions to at least one polymorphism and detecting thehybridization. In some embodiments, the polymorphism is detected by atechnique selected from the group consisting of scanning probe andnanopore DNA sequencing, pyrosequencing, Denaturing Gradient GelElectrophoresis (DGGE), Temporal Temperature Gradient Electrophoresis(TTGE), Zn(II)-cyclen polyacrylamide gel electrophoresis, homogeneousfluorescent PCR-based single nucleotide polymorphism analysis,phosphate-affinity polyacrylamide gel electrophoresis, high-throughputSNP genotyping platforms, molecular beacons, 5′ nuclease reaction,Taqman assay, MassArray (single base primer extension coupled withmatrix-assisted laser desorption/ionization time-of-flight massspectrometry), trityl mass tags, genotyping platforms (such as theInvader Assay®), single base primer extension (SBE) assays, PCRamplification (e.g. PCR amplification on magnetic nanoparticles (MNPs),restriction enzyme analysis of PCR products (RFLP methods),allele-specific PCR, multiple primer extension (MPEX), and isothermalsmart amplification. In some embodiments, the sample is any biologicalsample from which genomic DNA may be isolated, for example, but not tobe limited to a tissue sample, a sample of saliva, a cheek swab sample,blood, or other biological fluids that contain genomic DNA. In someembodiments, the sample comprises DNA. In some embodiments, the samplecomprises RNA. In some embodiments, the identity of the nucleotide atthe polymorphism in a patient is determined via genotyping. In someembodiments the genotyping is performed by PCR analysis, sequenceanalysis or LCR analysis. In some embodiments, the patient is identifiedas a patient with increased risk of progression of AMD (e.g.intermediate or advanced AMD such as wet (neovascular/exudative) AMD orgeographic atrophy) when at least one allele comprising a nucleotideselected from the group consisting of a G nucleotide at the SNPrs4698775 is present, a G nucleotide at the SNP rs17440077 is present,an A nucleotide at the SNP rs10737680 is present, a G nucleotide at theSNP rs1329428 is present, a G nucleotide at the SNP rs429608 is presentor the G nucleotide at the SNP rs2230199 is present. The patient isidentified as being at increased risk of AMD progression if the patienthas one or two copies of the G allele at rs4698775 or rs17440077associated with CFI, or equivalent alleles thereof, at rs1329428associated with CFH, or equivalent allele thereof, or at rs429608associated with C2/CFB, or equivalent allele thereof, or at rs2230199associated with C3, or equivalent allele thereof or one or two copies ofthe A allele at rs10737680 associated with CFH, or equivalent allelethereof. The patient is identified as being at decreased risk of AMDprogression if the patient does not have one or two copies of the Gallele at rs4698775 or rs17440077 associated with CFI, or equivalentalleles thereof, at rs1329428 associated with CFH, or equivalent allelethereof, at rs429608 associated with C2/CFB, or equivalent allelethereof, or at rs2230199 associated with C3, or equivalent allelethereof or one or two copies of the A allele at rs10737680 associatedwith CFH, or equivalent allele thereof.

One embodiment of the invention provides methods of predictingprogression of AMD (e.g. intermediate or advanced AMD such as wet(neovascular/exudative) AMD or geographic atrophy), the methodcomprising determining the genotype of a patient, wherein a patient whois determined to carry a risk allele (e.g. AMD-associated polymorphism)is identified as a patient with an increased risk of progression of AMD(e.g. intermediate or advanced AMD such as wet (neovascular/exudative)AMD or geographic atrophy). In some embodiments, increased risk ofprogression of AMD includes progression from early AMD to intermediateAMD and intermediate to advanced AMD. In some embodiments, the riskallele is the minor allele of a selected SNP. In some embodiments, therisk allele is the major allele of a selected SNP. In some embodiments,increased risk of progression of AMD includes progression from early tomore advanced disease in each of the AMD stages (includes early AMD,intermediate AMD and advanced AMD) wherein early AMD is characterized bymultiple small (<63 μm), or ≥1 intermediate drusen (≥63 μm and <125 μm);intermediate AMD is characterized by many intermediate or ≥1 largedrusen (≥125 μm) often accompanied by hyper- or hypopigmentation of theretinal pigment epithelium; and advanced AMD is characterized bygeographic atrophy (GA) or neovascular (wet) AMD). In some embodiments,the risk allele may be a complement factor I (CFI) risk allele, acomplement factor H(CFH) risk allele, a complement component 2 (C2) riskallele, a complement factor B (CFB) risk allele and/or a complementcomponent 3 (C3) risk allele. In some embodiments, the CFI risk alleleis the rs4698775:G allele, or equivalent allele thereof, or comprises aG at the selected SNP rs4698775, or comprises an alternate SNP inlinkage disequilibrium to rs4698775. In some embodiments, the alternateSNP comprises a minor allele or the allele which resides on the samehaplotype of the risk allele of the selected SNP rs4698775. In someembodiments, the CFI risk allele is the rs17440077 G: allele, orequivalent allele thereof, or comprises a G at the selected SNPrs17440077, or comprises an alternate SNP in linkage disequilibrium tors17440077. In some embodiments, the alternate SNP comprises a minorallele or the allele which resides on the same haplotype of the riskallele of the selected SNP rs17440077. In some embodiments, the CFH riskallele is the rs10737680:A allele, or equivalent allele thereof, orcomprises an A at the SNP rs10737680, or comprises an alternate SNP inlinkage disequilibrium to rs10737680. In some embodiments, the alternateSNP comprises a minor allele or the allele which resides on the samehaplotype of the risk allele of the selected SNP rs10737680. In someembodiments, the CFH risk allele is the rs1329428:G allele, orequivalent allele thereof, or comprises a G at the SNP rs1329428, orcomprises an alternate SNP in linkage disequilibrium to rs1329428. Insome embodiments, the alternate SNP comprises a minor allele or theallele which resides on the same haplotype of the risk allele of theselected SNP rs1329428. In some embodiments, the C2 risk allele is thers429608:G allele, or equivalent allele thereof, or comprises a G at theSNP rs429608 or comprises an alternate SNP in linkage disequilibrium tors429608. In some embodiments, the alternate SNP comprises a minorallele or the allele which resides on the same haplotype of the riskallele of the selected SNP rs429608. In some embodiments, the CFB riskallele is the rs429608:G allele, or equivalent allele thereof, orcomprises a G at SNP rs429608 or comprises an alternate SNP in linkagedisequilibrium to rs429608. In some embodiments, the alternate SNPcomprises a minor allele or the allele which resides on the samehaplotype of the risk allele of the selected SNP rs429608. In someembodiments, the C3 risk allele is the rs2230199:G allele, or equivalentallele thereof, or comprises a G at the SNP rs2230199 or comprises analternate SNP in linkage disequilibrium to rs2230199. In someembodiments, the alternate SNP comprises a minor allele or the allelewhich resides on the same haplotype of the risk allele of the selectedSNP rs2230199. In some embodiments, the linkage disequilibrium is a D′measure or an r² measure. In some embodiments, the D′ measure betweenthe selected SNP and the alternate SNP is ≥0.60. In some embodiments,the D′ measure between the selected SNP and the alternate SNP is ≥0.70,0.80 or 0.90. In some embodiments, the D′ measure between the selectedSNP and the alternate SNP is 1.0. In some embodiments, the r² measurebetween the selected SNP and the alternate SNP is ≥0.60. In someembodiments the r² measure between the selected SNP and the alternateSNP is ≥0.70, 0.80 or 0.90. In some embodiments, the r² measure betweenthe selected SNP and the alternate SNP is 1.0. In some embodiments, thealternate SNP is a SNP designated in Tables 4-7. In some embodiments,the SNP rs4698775 is located at position 110590479 on human chromosome 4(Genome Reference Consortium GRCh37; UCSC Genome HG19 Assembly; February2009) and the G allele changes the nucleotide sequence from T to G. Insome embodiments, the SNP rs17440077 is located at position 110537567 onhuman chromosome 4 (Genome Reference Consortium GRCh37; UCSC Genome HG19Assembly; February 2009) and the G allele changes the nucleotidesequence from A to G. In some embodiments, the SNP rs10737680 is locatedat position 196679455 on human chromosome 1 (Genome Reference ConsortiumGRCh37; UCSC Genome HG19 Assembly; February 2009) and the A allelechanges the nucleotide sequence form C to A. In some embodiments, theSNP rs1329428 is located at position 196702810 on human chromosome 1(Genome Reference Consortium GRCh37; UCSC Genome HG19 Assembly; February2009) and the G allele changes the nucleotide sequence from A to G. Insome embodiments, the SNP rs429608 is located at position 31930462 onhuman chromosome 6 (Genome Reference Consortium GRCh37; UCSC Genome HG19Assembly; February 2009) and the G allele changes the nucleotidesequence from A to G. In some embodiments, the SNP rs2230199 is locatedat position 6718387 on human chromosome 19 (Genome Reference ConsortiumGRCh37; UCSC Genome HG19 Assembly; February 2009) and the G allelechanges the nucleotide sequence from C to G and the encoded amino acidfrom an arginine to glycine. In some embodiments, the alternate SNP islocated on human chromosome 4 between SEC24B gene and EGF gene (forrs4698775) (Genome Reference Consortium GRCh37; UCSC Genome HG19Assembly; February 2009), human chromosome 4 between SEC24B gene and EGFgene (Genome Reference Consortium GRCh37; UCSC Genome HG19 Assembly;February 2009) (for rs17440077), human chromosome 1 between KCNT2 geneand LHX9 gene (Genome Reference Consortium GRCh37; UCSC Genome HG19Assembly; February 2009) (for rs10737680), human chromosome 1 betweenKCNT2 gene and LHX9 gene (Genome Reference Consortium GRCh37; UCSCGenome HG19 Assembly; February 2009) (for rs1329428), human chromosome 6between SLC44A4 gene and TNXB gene (Genome Reference Consortium GRCh37;UCSC Genome HG19 Assembly; February 2009) (for rs429608), humanchromosome 19 between TNFSF14 gene and VAV1 gene (Genome ReferenceConsortium GRCh37; UCSC Genome HG19 Assembly; February 2009) (forrs2230199). In some embodiments, the alternate SNP is located within500,000 base pairs upstream and downstream of the selected SNP. In someembodiments, the alternate SNP is located within 500,000 base pairsupstream or downstream of the selected SNP. In some embodiments, thepatient is determined to carry a CFI risk allele and/or a CFH riskallele and/or a C2 risk allele and/or a CFB risk allele and/or a C3 riskallele. In some embodiments, the patient is determined to carry 1, 2, 3,4, 5, 6, 7, 8, 9, 10, etc. AMD risk alleles. In some embodiments,presence of a risk allele in a patient comprises determining theidentity of the nucleotide at the polymorphism from nucleic acidprovided from a sample from a patient. In some embodiments, the nucleicacid sample comprises DNA. In some embodiments, the nucleic acid samplecomprises RNA. In some embodiments, the nucleic acid sample isamplified. In some embodiments, the nucleic acid sample is amplified bya polymerase chain reaction. In some embodiments, the polymorphism isdetected by polymerase chain reaction or sequencing. In someembodiments, the polymorphism is detected by amplification of a targetregion containing at least one polymorphism, and hybridization with atleast one sequence-specific oligonucleotide that hybridizes understringent conditions to at least one polymorphism and detecting thehybridization. In some embodiments, the polymorphism is detected by atechnique selected from the group consisting of scanning probe andnanopore DNA sequencing, pyrosequencing, Denaturing Gradient GelElectrophoresis (DGGE), Temporal Temperature Gradient Electrophoresis(TTGE), Zn(II)-cyclen polyacrylamide gel electrophoresis, homogeneousfluorescent PCR-based single nucleotide polymorphism analysis,phosphate-affinity polyacrylamide gel electrophoresis, high-throughputSNP genotyping platforms, molecular beacons, 5′ nuclease reaction,Taqman assay, MassArray (single base primer extension coupled withmatrix-assisted laser desorption/ionization time-of-flight massspectrometry), trityl mass tags, genotyping platforms (such as theInvader Assay®), single base primer extension (SBE) assays, PCRamplification (e.g. PCR amplification on magnetic nanoparticles (MNPs),restriction enzyme analysis of PCR products (RFLP methods),allele-specific PCR, multiple primer extension (MPEX), and isothermalsmart amplification. In some embodiments, the sample is any biologicalsample from which genomic DNA may be isolated, for example, but not tobe limited to a tissue sample, a sample of saliva, a cheek swab sample,blood, or other biological fluids that contain genomic DNA. In someembodiments, the identity of the nucleotide at the polymorphism in apatient is determined via genotyping. In some embodiments the genotypingis performed by PCR analysis, sequence analysis or LCR analysis. In someembodiments, the patient is identified as a patient with increased riskof progression of AMD (e.g. intermediate or advanced AMD such as wet(neovascular/exudative) AMD or geographic atrophy) when at least oneallele comprising a nucleotide selected from the group consisting of a Gnucleotide at the SNP rs4698775 is present, a G nucleotide at the SNPrs17440077 is present, an A nucleotide at the SNP rs10737680 is present,a G nucleotide at the SNP rs1329428 is present, a G nucleotide at theSNP rs429608 is present or the G nucleotide at the SNP rs2230199 ispresent. The patient is identified as being at increased risk ofprogressing to more advanced AMD if the patient has one or two copies ofthe G allele at rs4698775 or rs17440077 associated with CFI, orequivalent allele thereof, at rs1329428 associated with CFH, orequivalent allele thereof, at rs429608 associated with C2/CFB, orequivalent allele thereof, or at rs2230199 associated with C3, orequivalent allele thereof or one or two copies of the A allele atrs1329428 associated with CFH, or equivalent allele thereof. The patientis identified as being at decreased risk of progressing to more advancedAMD if the patient does not have one or two copies of the G allele atrs4698775 associated with CFI, or equivalent allele thereof, atrs1329428 associated with CFH, or equivalent allele thereof, at rs429608associated with C2/CFB, or equivalent allele thereof, or at rs2230199associated with C3, or equivalent allele thereof or one or two copies ofthe A allele at rs10737680 associated with CFH, or equivalent allelethereof.

The present invention involves, at least in part, a method of treating adegenerative disease (e.g. AMD) in a patient with an anti-factor Dantibody, or antigen-binding fragment thereof. In one aspect, theinvention involves methods and compositions for treating variousdegenerative disorders (e.g., age-related macular degeneration) with acomplement inhibitor. In one embodiment, the degenerative disease is anocular degenerative disease. In one embodiment, the ocular degenerativedisease is age-related macular degeneration. In any of the embodimentsdisclosed herein, a complement inhibitor is an anti-factor D antibody,or antigen-binding fragment thereof. In some embodiments, the antibodyis lampalizumab. Accordingly, one embodiment of the invention providesmethods of treating age-related macular degeneration in a patient, themethod comprising administering an effective amount of an anti-factor Dantibody, or antigen-binding fragment thereof, to a patient diagnosedwith age-related macular degeneration, wherein the patient carries oneor more risk alleles for age-related macular degeneration (e.g.AMD-associated polymorphism). In some embodiments, the risk allele isthe minor allele of a selected SNP. In some embodiments, the risk alleleis the major allele of a selected SNP. In some embodiments, the riskallele may be a CFI risk allele, a CFH risk allele, a C2 risk allele, aCFB risk allele and/or a C3 risk allele. In some embodiments, the riskallele is a CFI risk allele. In some embodiments, the CFI risk allele isthe rs4698775:G allele, or equivalent allele thereof, or comprises a Gat the selected SNP rs4698775, or comprises an alternate SNP in linkagedisequilibrium to rs4698775. In some embodiments, the alternate SNPcomprises a minor allele or the allele which resides on the samehaplotype of the risk allele of the selected SNP rs4698775. In someembodiments, the CFI risk allele is the rs17440077 G: allele, orequivalent allele thereof, or comprises a G at the selected SNPrs17440077, or comprises an alternate SNP in linkage disequilibrium tors17440077. In some embodiments, the alternate SNP comprises a minorallele or the allele which resides on the same haplotype of the riskallele of the selected SNP rs17440077. In some embodiments, the CFH riskallele is the rs10737680:A allele, or equivalent allele thereof, orcomprises an A at the selected SNP rs10737680, or comprises an alternateSNP in linkage disequilibrium to rs10737680. In some embodiments, thealternate SNP comprises a minor allele or the allele which resides onthe same haplotype of the risk allele of the selected SNP rs10737680. Insome embodiments, the CFH risk allele is the rs1329428:G allele, orequivalent allele thereof, or comprises a G at the SNP rs1329428, orcomprises an alternate SNP in linkage disequilibrium to rs1329428. Insome embodiments, the alternate SNP comprises a minor allele or theallele which resides on the same haplotype of the risk allele of theselected SNP rs1329428. In some embodiments, the C2 risk allele is thers429608:G allele, or equivalent allele thereof, or comprises a G at theselected SNP rs429608, or comprises an alternate SNP in linkagedisequilibrium to rs429608. In some embodiments, the alternate SNPcomprises a minor allele or the allele which resides on the samehaplotype of the risk allele of the selected SNP rs429608. In someembodiments, the CFB risk allele is the rs429608:G allele, or equivalentallele thereof, or comprises a G at the selected SNP rs429608, orcomprises an alternate SNP in linkage disequilibrium to rs429608. Insome embodiments, the alternate SNP comprises a minor allele or theallele which resides on the same haplotype of the risk allele of theselected SNP rs429608. In some embodiments, the C3 risk allele is thers2230199:G allele, or equivalent allele thereof, or comprises a G atthe selected SNP rs2230199 or comprises an alternate SNP in linkagedisequilibrium to rs2230199. In some embodiments, the alternate SNPcomprises a minor allele or the allele which resides on the samehaplotype of the risk allele of the selected SNP rs2230199. In someembodiments, the linkage disequilibrium is a D′ measure or an r²measure. In some embodiments, the D′ measure between the selected SNPand the alternate SNP is ≥0.60. In some embodiments, the D′ measurebetween the selected SNP and the alternate SNP is ≥0.70, 0.80 or 0.90.In some embodiments, the D′ measure between the selected SNP and thealternate SNP is 1.0. In some embodiments, the r² measure between theselected SNP and the alternate SNP is ≥0.60. In some embodiments the r²measure between the selected SNP and the alternate SNP is ≥0.70, 0.80 or0.90. In some embodiments, the r² measure between the selected SNP andthe alternate SNP is 1.0. In some embodiments, the alternate SNP is aSNP designated in Tables 4-7. In some embodiments, the SNP rs4698775 islocated at position 110590479 on human chromosome 4 (Genome ReferenceConsortium GRCh37; UCSC Genome HG19 Assembly; February 2009). The Gallele changes the nucleotide sequence from T to G. In some embodiments,the SNP rs17440077 is located at position 110537567 on human chromosome4 (Genome Reference Consortium GRCh37; UCSC Genome HG19 Assembly;February 2009). The G allele changes the nucleotide sequence from A toG. In some embodiments, the SNP rs10737680 is located at position196679455 on human chromosome 1 (Genome Reference Consortium GRCh37;UCSC Genome HG19 Assembly; February 2009). The A allele changes thenucleotide sequence form C to A. In some embodiments, the SNP rs1329428is located at position 196702810 on human chromosome 1 (Genome ReferenceConsortium GRCh37; UCSC Genome HG19 Assembly; February 2009). The Gallele changes the nucleotide sequence from A to G. In some embodiments,the SNP rs429608 is located at position 31930462 on human chromosome 6(Genome Reference Consortium GRCh37; UCSC Genome HG19 Assembly; February2009). The G allele changes the nucleotide sequence from A to G. In someembodiments, the SNP rs2230199 is located at position 6718387 on humanchromosome 19 (Genome Reference Consortium GRCh37; UCSC Genome HG19Assembly; February 2009). The G allele changes the nucleotide sequencefrom C to G and the encoded amino acid from arginine to glycine In someembodiments, the alternate SNP is located on human chromosome 4 betweenSEC24B gene and EGF gene (for rs4698775) (Genome Reference ConsortiumGRCh37; UCSC Genome HG19 Assembly; February 2009), human chromosome 4between SEC24B gene and EGF gene (Genome Reference Consortium GRCh37;UCSC Genome HG19 Assembly; February 2009) (for rs17440077), humanchromosome 1 between KCNT2 gene and LHX9 gene (Genome ReferenceConsortium GRCh37; UCSC Genome HG19 Assembly; February 2009) (forrs10737680), human chromosome 1 between KCNT2 gene and LHX9 gene (GenomeReference Consortium GRCh37; UCSC Genome HG19 Assembly; February 2009)(for rs1329428), human chromosome 6 between SLC44A4 gene and TNXB gene(Genome Reference Consortium GRCh37; UCSC Genome HG19 Assembly; February2009) (for rs429608), human chromosome 19 between TNFSF14 gene and VAV1gene (Genome Reference Consortium GRCh37; UCSC Genome HG19 Assembly;February 2009) (for rs2230199). In some embodiments, the alternate SNPis located within 500,000 base pairs upstream and downstream of theselected SNP. In some embodiments, the alternate SNP is located within500,000 base pairs upstream or downstream of the selected SNP In someembodiments, the patient is determined to carry a CFI risk allele and/ora CFH risk allele and/or a C2 risk allele and/or a CFB risk alleleand/or a C3 risk allele. In some embodiments, the patient is determinedto carry 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc. AMD risk alleles. In someembodiments, presence of a risk allele in a patient comprisesdetermining the identity of the nucleotide at the polymorphism fromnucleic acid provided from a sample from a patient. In some embodiments,the nucleic acid sample comprises DNA. In some embodiments, the nucleicacid sample comprises RNA. In some embodiments, the nucleic acid sampleis amplified. In some embodiments, the nucleic acid sample is amplifiedby a polymerase chain reaction. In some embodiments, the polymorphism isdetected by polymerase chain reaction or sequencing. In someembodiments, the polymorphism is detected by amplification of a targetregion containing at least one polymorphism, and hybridization with atleast one sequence-specific oligonucleotide that hybridizes understringent conditions to at least one polymorphism and detecting thehybridization. In some embodiments, the polymorphism is detected by atechnique selected from the group consisting of scanning probe andnanopore DNA sequencing, pyrosequencing, Denaturing Gradient GelElectrophoresis (DGGE), Temporal Temperature Gradient Electrophoresis(TTGE), Zn(II)-cyclen polyacrylamide gel electrophoresis, homogeneousfluorescent PCR-based single nucleotide polymorphism analysis,phosphate-affinity polyacrylamide gel electrophoresis, high-throughputSNP genotyping platforms, molecular beacons, 5′ nuclease reaction,Taqman assay, MassArray (single base primer extension coupled withmatrix-assisted laser desorption/ionization time-of-flight massspectrometry), trityl mass tags, genotyping platforms (such as theInvader Assay®), single base primer extension (SBE) assays, PCRamplification (e.g. PCR amplification on magnetic nanoparticles (MNPs),restriction enzyme analysis of PCR products (RFLP methods),allele-specific PCR, multiple primer extension (MPEX), and isothermalsmart amplification. In some embodiments, the sample is any biologicalsample from which genomic DNA may be isolated, for example, but not tobe limited to a tissue sample, a sample of saliva, a cheek swab sample,blood, or other biological fluids that contain genomic DNA. In someembodiments, the identity of the nucleotide at the polymorphism in apatient is determined via genotyping. In some embodiments the genotypingis performed by PCR analysis, sequence analysis or LCR analysis. In someembodiments, the patient is identified as having an increased at riskfor AMD progression and more likely to respond to a therapy comprisingan anti-factor D antibody, or antigen-binding fragment thereof, when atleast one allele comprising a nucleotide selected from the groupconsisting of a G nucleotide at the SNP rs4698775 is present, a Gnucleotide at the SNP rs17440077 is present, an A nucleotide at the SNPrs10737680 is present, a G nucleotide at the SNP rs1329428 is present, aG nucleotide at the SNP rs429608 is present or the G nucleotide at theSNP rs2230199 is present. The patient is identified as having anincreased risk for AMD progression and more likely to respond to atreatment comprising an anti-factor D antibody, or antigen-bindingfragment thereof, if the patient has one or two copies of the G alleleat rs4698775 or rs17440077 associated with CFI, or equivalent allelethereof, at rs1329428 associated with CFH, or equivalent allele thereof,at rs429608 associated with C2/CFB, or equivalent allele thereof, or atrs2230199 associated with C3, or equivalent allele thereof or one or twocopies of the A allele at rs10737680 associated with CFH, or equivalentallele thereof. The patient is identified as having a decreased risk ofprogressing to more advanced AMD and less likely to respond to atreatment comprising an anti-factor D antibody, or antigen-bindingfragment thereof, if the patient does not have one or two copies of theG allele at rs4698775 associated with CFI, or equivalent allele thereof,at rs1329428 associated with CFH, or equivalent allele thereof, atrs429608 associated with C2/CFB, or equivalent allele thereof, or atrs2230199 associated with C3, or equivalent allele thereof or one or twocopies of the A allele at rs10737680 associated with CFH, or equivalentallele thereof. In one embodiment, the study eye in the patient has aBCVA between 20/2.5 and 20/400. In one embodiment, the study eye in thepatient has a BCVA between 20/25 and 20/100. In one embodiment, thestudy eye in the patient has a BCVA between 20/50 and 20/400. In oneembodiment, the study eye in the patient has a BCVA between 20/50 and20/100. In one embodiment, the study eye in the patient has a BCVAbetter than 20/25 or worse than 20/400. In one embodiment, the BCVA wasdetermined using ETDRS charts. In some embodiments, the antibody orantigen-binding fragment thereof is administered intravitreally. In someembodiments, the age-related macular degeneration is dry AMD. In someembodiments, the dry AMD is advanced dry AMD. In some embodiments, theadvanced dry AMD is geographic atrophy. In some embodiments, the patienthas a reduced mean change in geographic atrophy (GA) area followingadministration of the antibody as compared to control patients that donot receive the antibody treatment. In some embodiments, the mean changein GA area is determined by measurements of GA area via standard imagingmethods (e.g. fundus autofluorescence (FAF) or color fundus photography(CFP). In some embodiments, the age-related macular degeneration isearly AMD or intermediate AMD. In some embodiments, the patient withearly AMD or intermediate AMD has a reduction or delay in appearance ofclinical signs (e.g. may include measuring the number and size of drusen(for early and intermediate AMD) and monitoring hypo- andhyperpigmentation associated with drusen (for intermediate AMD)). Insome embodiments, the methods further comprise administering a secondmedicament to the subject. In some embodiments, the second medicament isVEGF inhibitor.

A further embodiment of the invention provides methods of identifying adegenerative disease patient (e.g. AMD patient) who may benefit fromand/or respond to treatment with an anti-factor D antibody, the methodcomprising determining the genotype of a patient, wherein a patient whois determined to carry a risk allele is identified as a patient who maybenefit from treatment with an anti-factor D antibody or antigen-bindingfragment thereof. In some embodiments, the method further comprisesselecting the therapy comprising an anti-factor D antibody, orantigen-binding fragment thereof. In some embodiments, the antibody islampalizumab. In one embodiment, the degenerative disease is an oculardegenerative disease. In one embodiment, the ocular degenerative diseaseis age-related macular degeneration. In some embodiments, the riskallele is the minor allele of a selected SNP. In some embodiments, therisk allele is the major allele of a selected SNP. In some embodiments,the risk allele (e.g. AMD-associated polymorphism) may be a CFI riskallele, a CFH risk allele, a C2 risk allele, a CFB risk allele and/or aC3 risk allele. In some embodiments, the risk allele is a CFI riskallele. In some embodiments, the CFI allele is the rs4698775:G allele,or equivalent allele thereof or comprises a G at the selected SNPrs4698775, or comprises an alternate SNP in linkage disequilibrium tors4698775. In some embodiments, the alternate SNP comprises a minorallele or the allele which resides on the same haplotype of the riskallele of the selected SNP rs4698775. In some embodiments, the CFIallele is the rs17440077:G allele, or equivalent allele thereof orcomprises a G at the selected SNP rs17440077, or comprises an alternateSNP in linkage disequilibrium to rs17440077. In some embodiments, thealternate SNP comprises a minor allele or the allele which resides onthe same haplotype of the risk allele of the selected SNP rs17440077. Insome embodiments, the CFH risk allele is the rs10737680:A allele, orequivalent allele thereof, or comprises an A at the selected SNPrs10737680, or comprises an alternate SNP in linkage disequilibrium tors10737680. In some embodiments, the alternate SNP comprises a minorallele or the allele which resides on the same haplotype of the riskallele of the selected SNP rs10737680. In some embodiments, the CFH riskallele is the rs1329428:G allele, or equivalent allele thereof, orcomprises a G at the selected SNP rs1329428, or comprises an alternateSNP in linkage disequilibrium to rs1329428. In some embodiments, thealternate SNP comprises a minor allele or the allele which resides onthe same haplotype of the risk allele of the selected SNP rs1329428. Insome embodiments, the C2 risk allele is the rs429608:G allele, orequivalent allele thereof, or comprises a G at the selected SNPrs429608, or comprises an alternate SNP in linkage disequilibrium tors429608. In some embodiments, the alternate SNP comprises a minorallele or the allele which resides on the same haplotype of the riskallele of the selected SNP rs429608. In some embodiments, the CFB riskallele is the rs429608:G allele, or equivalent allele thereof, orcomprises a G at the selected SNP rs429608, or comprises an alternateSNP in linkage disequilibrium to rs429608. In some embodiments, thealternate SNP comprises a minor allele or the allele which resides onthe same haplotype of the risk allele of the selected SNP rs429608. Insome embodiments, the C3 risk allele is the rs2230199:G allele, orequivalent allele thereof, or comprises a G at the selected SNPrs2230199 or comprises an alternate SNP in linkage disequilibrium tors2230199. In some embodiments, the alternate SNP comprises a minorallele or the allele which resides on the same haplotype of the riskallele of the selected SNP rs2230199. In some embodiments, the linkagedisequilibrium is a D′ measure or an r² measure. In some embodiments,the D′ measure between the selected SNP and the alternate SNP is ≥0.60.In some embodiments, the D′ measure between the selected SNP and thealternate SNP is ≥0.70, 0.80 or 0.90. In some embodiments, the D′measure between the selected SNP and the alternate SNP is 1.0. In someembodiments, the r² measure between the selected SNP and the alternateSNP is ≥0.60. In some embodiments the r² measure between the selectedSNP and the alternate SNP is ≥0.70, 0.80 or 0.90. In some embodiments,the r² measure between the selected SNP and the alternate SNP is 1.0. Insome embodiments, the alternate SNP is a SNP designated in Tables 4-7.In some embodiments, the SNP rs4698775 is located at position 110590479on human chromosome 4 (Genome Reference Consortium GRCh37; UCSC GenomeHG19 Assembly; February 2009) and he G allele changes the nucleotidesequence from T to G. In some embodiments, the SNP rs17440077 is locatedat position 110537567 on human chromosome 4 (Genome Reference ConsortiumGRCh37; UCSC Genome HG19 Assembly; February 2009) and the G allelechanges the nucleotide sequence from A to G. In some embodiments, theSNP rs10737680 is located at position 196679455 on human chromosome 1(Genome Reference Consortium GRCh37; UCSC Genome HG19 Assembly; February2009) and the A allele changes the nucleotide sequence form C to A. Insome embodiments, the SNP rs1329428 is located at position 196702810 onhuman chromosome 1 (Genome Reference Consortium GRCh37; UCSC Genome HG19Assembly; February 2009) and the G allele changes the nucleotidesequence from A to G. In some embodiments, the SNP rs429608 is locatedat position 31930462 on human chromosome 6 (Genome Reference ConsortiumGRCh37; UCSC Genome HG19 Assembly; February 2009) and the G allelechanges the nucleotide sequence from A to G. In some embodiments, theSNP rs2230199 is located at position 6718387 on human chromosome 19(Genome Reference Consortium GRCh37; UCSC Genome HG19 Assembly; February2009) and the G allele changes the nucleotide sequence from C to G andthe encoded amino acid from arginine to glycine. In some embodiments,the alternate SNP is located on human chromosome 4 between SEC24B geneand EGF gene (for rs4698775) (Genome Reference Consortium GRCh37; UCSCGenome HG19 Assembly; February 2009), human chromosome 4 between SEC24Bgene and EGF gene (Genome Reference Consortium GRCh37; UCSC Genome HG19Assembly; February 2009) (for rs17440077), human chromosome 1 betweenKCNT2 gene and LHX9 gene (Genome Reference Consortium GRCh37; UCSCGenome HG19 Assembly; February 2009) (for rs10737680), human chromosome1 between KCNT2 gene and LHX9 gene (Genome Reference Consortium GRCh37;UCSC Genome HG19 Assembly; February 2009) (for rs1329428), humanchromosome 6 between SLC44A4 gene and TNXB gene (Genome ReferenceConsortium GRCh37; UCSC Genome HG19 Assembly; February 2009) (forrs429608), human chromosome 19 between TNFSF14 gene and VAV1 gene(Genome Reference Consortium GRCh37; UCSC Genome HG19 Assembly; February2009) (for rs2230199). In some embodiments, the alternate SNP is locatedwithin 500,000 base pairs upstream or downstream of the selected SNP. Insome embodiments, the patient is determined to carry a CFI risk alleleand/or a CFH risk allele and/or a C2 risk allele and/or a CFB riskallele and/or a C3 risk allele. In some embodiments, the patient isdetermined to carry 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc. AMD riskalleles. In some embodiments, presence of a risk allele in a patientcomprises determining the identity of the nucleotide at the polymorphismfrom nucleic acid provided from a sample from a patient. In someembodiments, the nucleic acid sample comprises DNA. In some embodiments,the nucleic acid sample comprises RNA. In some embodiments, the nucleicacid sample is amplified. In some embodiments, the nucleic acid sampleis amplified by a polymerase chain reaction. In some embodiments, thepolymorphism is detected by polymerase chain reaction or sequencing. Insome embodiments, the polymorphism is detected by amplification of atarget region containing at least one polymorphism, and hybridizationwith at least one sequence-specific oligonucleotide that hybridizesunder stringent conditions to at least one polymorphism and detectingthe hybridization. In some embodiments, the polymorphism is detected bya technique selected from the group consisting of scanning probe andnanopore DNA sequencing, pyrosequencing, Denaturing Gradient GelElectrophoresis (DGGE), Temporal Temperature Gradient Electrophoresis(TTGE), Zn(II)-cyclen polyacrylamide gel electrophoresis, homogeneousfluorescent PCR-based single nucleotide polymorphism analysis,phosphate-affinity polyacrylamide gel electrophoresis, high-throughputSNP genotyping platforms, molecular beacons, 5′ nuclease reaction,Taqman assay, MassArray (single base primer extension coupled withmatrix-assisted laser desorption/ionization time-of-flight massspectrometry), trityl mass tags, genotyping platforms (such as theInvader Assay®), single base primer extension (SBE) assays, PCRamplification (e.g. PCR amplification on magnetic nanoparticles (MNPs),restriction enzyme analysis of PCR products (RFLP methods),allele-specific PCR, multiple primer extension (MPEX), and isothermalsmart amplification. In some embodiments, the sample is any biologicalsample from which genomic DNA may be isolated, for example, but not tobe limited to a tissue sample, a sample of saliva, a cheek swab sample,blood, or other biological fluids that contain genomic DNA. In someembodiments, the sample comprises DNA. In some embodiments, the samplecomprises RNA. In some embodiments, the identity of the nucleotide atthe polymorphism in a patient is determined via genotyping. In someembodiments the genotyping is performed by PCR analysis, sequenceanalysis or LCR analysis. In some embodiments, the patient is identifiedas having an increased risk for AMD progression and is more likely tobenefit from and/or respond to treatment comprising an anti-factor Dantibody, or antigen-binding fragment thereof when at least one allelecomprising a nucleotide selected from the group consisting of a Gnucleotide at the SNP rs4698775 is present, a G nucleotide at the SNPrs17440077 is present, an A nucleotide at the SNP rs10737680 is present,a G nucleotide at the SNP rs1329428 is present, a G nucleotide at theSNP rs429608 is present or the G nucleotide at the SNP rs2230199 ispresent. The patient is identified as being at increased risk of AMDprogression if the patient has one or two copies of the G allele atrs4698775 associated with CFI, or equivalent allele thereof, atrs1329428 associated with CFH, or equivalent allele thereof, at rs429608associated with C2/CFB, or equivalent allele thereof, or at rs2230199associated with C3, or equivalent allele thereof or has one or twocopies of the A allele at rs10737680 associated with CFH, or equivalentallele thereof. The patient is identified as having a decreased risk ofprogressing to more advanced AMD if the patient does not have one or twocopies of the G allele at rs4698775 associated with CFI, or equivalentallele thereof, at rs1329428 associated with CFH, or equivalent allelethereof, at rs429608 associated with C2/CFB, or equivalent allelethereof, or at rs2230199 associated with C3, or equivalent allelethereof or one or two copies of the A allele at rs10737680 associatedwith CFH, or equivalent allele thereof. In one embodiment, the study eyein the patient has a BCVA between 20/25 and 20/400. In one embodiment,the study eye in the patient has a BCVA between 20/25 and 20/100. In oneembodiment, the study eye in the patient has a BCVA between 20/50 and20/400. In one embodiment, the study eye in the patient has a BC VAbetween 20/50 and 20/100. In one embodiment, the study eye in thepatient has a BC VA better than 20/25 or worse than 20/400. In oneembodiment, the BCVA was determined using ETDRS charts. In someembodiments, the antibody or antigen-binding fragment thereof isadministered intravitreally. In some embodiments, the age-relatedmacular degeneration is dry AMD. In some embodiments, the dry AMD isadvanced dry AMD. In some embodiments, the advanced dry AMD isgeographic atrophy. In some embodiments, the age-related maculardegeneration is early AMD or intermediate AMD. In some embodiments, thepatient with early AMD or intermediate AMD has a reduction or delay inappearance of clinical signs (e.g. may include measuring the number andsize of drusen (for early and intermediate AMD) and monitoring hypo- andhyperpigmentation associated with drusen (for intermediate AMD)).

Another embodiment of the invention provides methods of optimizingtherapeutic efficacy for treatment of a degenerative disease (e.g. AMD),the method comprising determining the genotype of a patient, wherein apatient who is determined to carry a risk allele (e.g. AMD-associatedpolymorphism) is more likely to respond to treatment with theanti-factor D antibody, or antigen-binding fragment thereof orantigen-binding fragment thereof. In one embodiment, the degenerativedisease is an ocular degenerative disease. In one embodiment, the oculardegenerative disease is age-related macular degeneration. In someembodiments, the antibody is lampalizumab. In some embodiments, the riskallele is the minor allele of a selected SNP. In some embodiments, therisk allele is the major allele of a selected SNP. In some embodiments,the risk allele may be a CFI risk allele, a CFH risk allele, a C2 riskallele, a CFB allele and/or a C3 risk allele. In some embodiments, therisk allele is a CFI risk allele. In some embodiments, the CFI riskallele is the rs4698775:G allele, or equivalent allele thereof orcomprises a G at the selected SNP rs4698775, or comprises an alternateSNP in linkage disequilibrium to rs4698775. In some embodiments, thealternate SNP comprises a minor allele or the allele which resides onthe same haplotype of the risk allele of the selected SNP rs4698775. Insome embodiments, the CFI risk allele is the rs17440077:G allele, orequivalent allele thereof or comprises a G at the selected SNPrs17440077, or comprises an alternate SNP in linkage disequilibrium tors17440077. In some embodiments, the alternate SNP comprises a minorallele or the allele which resides on the same haplotype of the riskallele of the selected SNP rs17440077. In some embodiments, the CFH riskallele is the rs10737680:A allele, or equivalent allele thereof, orcomprises an A at the selected SNP rs10737680, or comprises an alternateSNP in linkage disequilibrium to rs10737680. In some embodiments, thealternate SNP comprises a minor allele or the allele which resides onthe same haplotype of the risk allele of the selected SNP rs10737680. Insome embodiments, the CFH risk allele is the rs1329428:G allele, orequivalent allele thereof, or comprises an G at the selected SNPrs1329428, or comprises an alternate SNP in linkage disequilibrium tors1329428 In some embodiments, the alternate SNP comprises a minorallele or the allele which resides on the same haplotype of the riskallele of the selected SNP rs1329428. In some embodiments, the C2 riskallele is the rs429608:G allele, or equivalent allele thereof, orcomprises a G at the selected SNP rs429608, or comprises an alternateSNP in linkage disequilibrium to rs429608. In some embodiments, thealternate SNP comprises a minor allele or the allele which resides onthe same haplotype of the risk allele of the selected SNP rs429608. Insome embodiments, the CFB risk allele is the rs429608:G allele, orequivalent allele thereof, or comprises a G at the selected SNPrs429608, or comprises an alternate SNP in linkage disequilibrium tors429608. In some embodiments, the alternate SNP comprises a minorallele or the allele which resides on the same haplotype of the riskallele of the selected SNP rs429608. In some embodiments, the C3 riskallele is the rs2230199:G allele, or equivalent allele thereof, orcomprises a G at the selected SNP rs2230199 or comprises an alternateSNP in linkage disequilibrium to rs2230199. In some embodiments, thealternate SNP comprises a minor allele or the allele which resides onthe same haplotype of the risk allele of the selected SNP rs2230199. Insome embodiments, the linkage disequilibrium is a D′ measure or an r²measure. In some embodiments, the D′ measure between the selected SNPand the alternate SNP is ≥0.60. In some embodiments, the D′ measurebetween the selected SNP and the alternate SNP is ≥0.70, 0.80 or 0.90.In some embodiments, the D′ measure between the selected SNP and thealternate SNP is 1.0. In some embodiments, the r² measure between theselected SNP and the alternate SNP is ≥0.60. In some embodiments the r²measure between the selected SNP and the alternate SNP is ≥0.70, 0.80 or0.90. In some embodiments, the r² measure between the selected SNP andthe alternate SNP is 1.0. In some embodiments, the alternate SNP is aSNP designated in Tables 4-7. In some embodiments, the SNP rs4698775 islocated at position 110590479 on human chromosome 4 (Genome ReferenceConsortium GRCh37; UCSC Genome HG19 Assembly; February 2009) and the Gallele changes the nucleotide sequence from T to G. In some embodiments,the SNP rs17440077 is located at position 110537567 on human chromosome4 (Genome Reference Consortium GRCh37; UCSC Genome HG19 Assembly;February 2009) and the G allele changes the nucleotide sequence from Ato G. In some embodiments, the SNP rs10737680 is located at position196679455 on human chromosome 1 (Genome Reference Consortium GRCh37;UCSC Genome HG19 Assembly; February 2009) and the A allele changes thenucleotide sequence form C to A. In some embodiments, the SNP rs1329428is located at position 196702810 on human chromosome 1 (Genome ReferenceConsortium GRCh37; UCSC Genome HG19 Assembly; February 2009) and the Gallele changes the nucleotide sequence from A to G. In some embodiments,the SNP rs429608 is located at position 31930462 on human chromosome 6(Genome Reference Consortium GRCh37; UCSC Genome HG19 Assembly; February2009) and the G allele changes the nucleotide sequence from A to G. Insome embodiments, the SNP rs2230199 is located at position 6718387 onhuman chromosome 19 (Genome Reference Consortium GRCh37; UCSC GenomeHG19 Assembly; February 2009) and the G allele changes the nucleotidesequence from C to G and changes the encoded amino acid from arginine toglycine. In some embodiments, the alternate SNP is located on humanchromosome 4 between SEC24B gene and EGF gene (for rs4698775) (GenomeReference Consortium GRCh37; UCSC Genome HG19 Assembly; February 2009),human chromosome 4 between SEC24B gene and EGF gene (Genome ReferenceConsortium GRCh37; UCSC Genome HG19 Assembly; February 2009) (forrs17440077), human chromosome 1 between KCNT2 gene and LHX9 gene (GenomeReference Consortium GRCh37; UCSC Genome HG19 Assembly; February 2009)(for rs10737680), human chromosome 1 between KCNT2 gene and LHX9 gene(Genome Reference Consortium GRCh37; UCSC Genome HG19 Assembly; February2009) (for rs1329428), human chromosome 6 between SLC44A4 gene and TNXBgene (Genome Reference Consortium GRCh37; UCSC Genome HG19 Assembly;February 2009) (for rs429608), human chromosome 19 between TNFSF14 geneand VAV1 gene (Genome Reference Consortium GRCh37; UCSC Genome HG19Assembly; February 2009) (for rs2230199). In some embodiments, thealternate SNP is located within 500,000 base pairs upstream ordownstream of the selected SNP. In some embodiments, the alternate SNPis located within 500 base pairs upstream and downstream of the selectedSNP In some embodiments, the patient is determined to carry a CFI riskallele and/or a CFH risk allele and/or a C2 risk allele and/or a CFBrisk allele and/or a C3 risk allele. In some embodiments, the patient isdetermined to carry 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc. AMD riskalleles. In some embodiments, presence of a risk allele in a patientcomprises determining the identity of the nucleotide at the polymorphismnucleic acid provided from a sample from a patient. In some embodiments,the nucleic acid sample comprises DNA. In some embodiments, the nucleicacid sample comprises RNA. In some embodiments, the nucleic acid sampleis amplified. In some embodiments, the nucleic acid sample is amplifiedby a polymerase chain reaction. In some embodiments, the polymorphism isdetected by polymerase chain reaction or sequencing. In someembodiments, the polymorphism is detected by amplification of a targetregion containing at least one polymorphism, and hybridization with atleast one sequence-specific oligonucleotide that hybridizes understringent conditions to at least one polymorphism and detecting thehybridization. In some embodiments, the polymorphism is detected by atechnique selected from the group consisting of scanning probe andnanopore DNA sequencing, pyrosequencing, Denaturing Gradient GelElectrophoresis (DGGE), Temporal Temperature Gradient Electrophoresis(TTGE), Zn(II)-cyclen polyacrylamide gel electrophoresis, homogeneousfluorescent PCR-based single nucleotide polymorphism analysis,phosphate-affinity polyacrylamide gel electrophoresis, high-throughputSNP genotyping platforms, molecular beacons, 5′ nuclease reaction,Taqman assay, MassArray (single base primer extension coupled withmatrix-assisted laser desorption/ionization time-of-flight massspectrometry), trityl mass tags, genotyping platforms (such as theInvader Assay®), single base primer extension (SBE) assays, PCRamplification (e.g. PCR amplification on magnetic nanoparticles (MNPs),restriction enzyme analysis of PCR products (RFLP methods),allele-specific PCR, multiple primer extension (MPEX), and isothermalsmart amplification. In some embodiments, the sample is any biologicalsample from which genomic DNA may be isolated, for example, but not tobe limited to a tissue sample, a sample of saliva, a cheek swab sample,blood, or other biological fluids that contain genomic DNA. In someembodiments, the sample comprises DNA. In some embodiments, the samplecomprises RNA. In some embodiments, the identity of the nucleotide atthe polymorphism in a patient is determined via genotyping. In someembodiments the genotyping is performed by PCR analysis, sequenceanalysis or LCR analysis. In some embodiments, the patient is identifiedas having an increased risk for AMD progression and is more likely tobenefit from treatment comprising an anti-factor D antibody, orantigen-binding fragment thereof when at least one allele comprising anucleotide selected from the group consisting of a G nucleotide at theSNP rs4698775 is present, a G nucleotide at the SNP rs17440077 ispresent, an A nucleotide at the SNP rs10737680 is present, a Gnucleotide at the SNP rs1329428 is present, a G nucleotide at the SNPrs429608 is present or the G nucleotide at the SNP rs2230199 is present.The patient is identified as being at increased risk of AMD progressionif the patient has one or two copies of the G allele at rs4698775 orrs17440077 associated with CFI, or equivalent allele thereof, atrs1329428 associated with CFH, or equivalent allele thereof, at rs429608associated with C2/CFB, or equivalent allele thereof, or at rs2230199associated with C3, or equivalent allele thereof or one or two copies ofthe A allele at rs10737680 associated with CFH, or equivalent allelethereof. In one embodiment, the study eye in the patient has a BCVAbetween 20/25 and 20/400. It one embodiment, the study eye in thepatient has a BCVA between 20/25 and 20/100. In one embodiment, thestudy eye in the patient has a BCVA between 20/50 and 20/400. In oneembodiment, the study eye in the patient has a BCVA between 20/50 and20/100. In one embodiment, the study eye in the patient has a BCVAbetter than 20/25 or worse than 20/400. In one embodiment, the BCVA wasdetermined using ETDRS charts. In some embodiments, the antibody orantigen-binding fragment thereof is administered intravitreally. In someembodiments, the age-related macular degeneration is dry AMD. In someembodiments, the dry AMD is advanced dry AMD. In some embodiments, theadvanced dry AMD is geographic atrophy. In some embodiments, the patienthas a reduced mean change in geographic atrophy (GA) area followingadministration of the antibody as compared to control patients that didnot receive the antibody treatment. In some embodiments, the mean changein GA area is determined by measuring GA area via standard imagingmethods (e.g. fundus autofluorescence (FAF) or color fundus photography(CFP). In some embodiments, the age-related macular degeneration isearly AMD or intermediate AMD. In some embodiments, the patient withearly AMD or intermediate AMD has a reduction or delay in appearance ofclinical signs (e.g. may include measuring the number and size of drusen(for early and intermediate AMD) and monitoring hypo- andhyperpigmentation associated with drusen (for intermediate AMD)). Insome embodiments, the methods further comprise administering a secondmedicament to the subject. In some embodiments, the second medicament isVEGF inhibitor.

Even another embodiment of the invention provides methods of predictingresponsiveness of a degenerative disease (e.g. AMD) patient to treatmentwith an anti-factor D antibody or antigen-binding fragment thereof, themethod comprising determining the genotype of the patient, wherein apatient who is determined to carry a risk allele is identified as apatient who has an increased risk for AMD progression (e.g. GAprogression) and is more likely to respond to treatment with theanti-factor D antibody or antigen-binding fragment thereof. In oneembodiment, the degenerative disease is an ocular degenerative disease.In one embodiment, the ocular degenerative disease is age-relatedmacular degeneration. In some embodiments, the antibody is lampalizumab.In some embodiments, the risk allele is the minor allele of a selectedSNP. In some embodiments, the risk allele is the major allele of aselected SNP. In some embodiments, the risk allele (e.g. AMD-associatedpolymorphism) may be a CFI risk allele, a CFH risk allele, a C2 riskallele, a CFB risk allele and/or a C3 risk allele. In some embodiments,the risk allele is a CFI risk allele. In some embodiments, the CFI riskallele is the rs4698775:G allele, or equivalent allele thereof orcomprises a G at the selected SNP rs4698775, or comprises an alternateSNP in linkage disequilibrium to rs4698775. In some embodiments, thealternate SNP comprises a minor allele or the allele which resides onthe same haplotype of the risk allele of the selected SNP rs4698775. Insome embodiments, the CFI risk allele is the rs17440077:G allele, orequivalent allele thereof or comprises a G at the selected SNPrs17440077, or comprises an alternate SNP in linkage disequilibrium tors17440077. In some embodiments, the alternate SNP comprises a minorallele or the allele which resides on the same haplotype of the riskallele of the selected SNP rs17440077. In some embodiments, the CFH riskallele is the rs10737680:A allele, or equivalent allele thereof, orcomprises an A at the selected SNP rs10737680, or comprises an alternateSNP in linkage disequilibrium to rs10737680. In some embodiments, thealternate SNP comprises a minor allele or the allele which resides onthe same haplotype of the risk allele of the selected SNP rs10737680. Insome embodiments, the CFH risk allele is the rs1329428:G allele, orequivalent allele thereof, or comprises a G at the selected SNPrs1329428, or comprises an alternate SNP in linkage disequilibrium tors1329428. In some embodiments, the alternate SNP comprises a minorallele or the allele which resides on the same haplotype of the riskallele of the selected SNP rs1329428. In some embodiments, the C2 riskallele is the rs429608:G allele, or equivalent allele thereof, orcomprises a G at the selected SNP rs429608, or comprises an alternateSNP in linkage disequilibrium to rs429608. In some embodiments, thealternate SNP comprises a minor allele or the allele which resides onthe same haplotype of the risk allele of the selected SNP rs429608. Insome embodiments, the CFB risk allele is the rs429608:G allele, orequivalent allele thereof, or comprises a G at the selected SNPrs429608, or comprises an alternate SNP in linkage disequilibrium tors429608. In some embodiments, the alternate SNP comprises a minorallele or the allele which resides on the same haplotype of the riskallele of the selected SNP rs429608. In some embodiments, the C3 riskallele is the rs2230199:G allele, or equivalent allele thereof, orcomprises a G at the selected SNP rs2230199 or comprises an alternateSNP in linkage disequilibrium to rs2230199. In some embodiments, thealternate SNP comprises a minor allele or the allele which resides onthe same haplotype of the risk allele of the selected SNP rs2230199. Insome embodiments, the linkage disequilibrium is a D′ measure or an r²measure. In some embodiments, the D′ measure is between the selected SNPand the alternate SNP is ≥0.60. In some embodiments, the D′ measurebetween the selected SNP and the alternate SNP is ≥0.70, 0.80, or 0.90.In some embodiments, the D′ measure between the selected SNP and thealternate SNP is 1.0. In some embodiments, the r² measure is between theselected SNP and the alternate SNP is ≥0.60. In some embodiments, the r²measure between the selected SNP and the alternate SNP is ≥0.70, 0.80,or 0.90. In some embodiments, the r² measure between the selected SNPand the alternate SNP is 1.0. In some embodiments, the alternate SNP isa SNP designated in Tables 4-7. In some embodiments, the SNP rs4698775is located at position 110590479 on human chromosome 4 (Genome ReferenceConsortium GRCh37; UCSC Genome HG19 Assembly; February 2009) and the Gallele changes the nucleotide sequence from T to G. In some embodiments,the SNP rs17440077 is located at position 110537567 on human chromosome4 (Genome Reference Consortium GRCh37; UCSC Genome HG19 Assembly;February 2009) and the G allele changes the nucleotide sequence from Ato G. In some embodiments, the SNP rs10737680 is located at position196679455 on human chromosome 1 (Genome Reference Consortium GRCh37;UCSC Genome HG19 Assembly; February 2009) and the A allele changes thenucleotide sequence form C to A. In some embodiments, the SNP rs1329428is located at position 196702810 on human chromosome 1 (Genome ReferenceConsortium GRCh37; UCSC Genome HG19 Assembly; February 2009) and the Gallele changes the nucleotide sequence from A to G. In some embodiments,the SNP rs429608 is located at position 31930462 on human chromosome 6(Genome Reference Consortium GRCh37; UCSC Genome HG19 Assembly; February2009) and the G allele changes the nucleotide sequence from A to G. Insome embodiments, the SNP rs2230199 is located at position 6718387 onhuman chromosome 19 (Genome Reference Consortium GRCh37; UCSC GenomeHG19 Assembly; February 2009) and the G allele changes the nucleotidesequence from C to G and changes the encoded amino acid from arginine toglycine. In some embodiments, the alternate SNP is located on humanchromosome 4 between SEC24B gene and EGF gene (for rs4698775) (GenomeReference Consortium GRCh37; UCSC Genome HG19 Assembly; February 2009),human chromosome 4 between SEC24B gene and EGF gene (Genome ReferenceConsortium GRCh37; UCSC Genome HG19 Assembly; February 2009) (forrs17440077), human chromosome 1 between KCNT2 gene and LHX9 gene (GenomeReference Consortium GRCh37; UCSC Genome HG19 Assembly; February 2009)(for rs10737680), human chromosome 1 between KCNT2 gene and LHX9 gene(Genome Reference Consortium GRCh37; UCSC Genome HG19 Assembly; February2009) (for rs1329428), human chromosome 6 between SLC44A4 gene and TNXBgene (Genome Reference Consortium GRCh37; UCSC Genome HG19 Assembly;February 2009) (for rs429608), human chromosome 19 between TNFSF14 geneand VAV1 gene (Genome Reference Consortium GRCh37; UCSC Genome HG19Assembly; February 2009) (for rs2230199). In some embodiments, thealternate SNP is located within 500,000 base pairs upstream anddownstream of the selected SNP. In some embodiments, the patient isdetermined to carry a CFI risk allele and/or a CFH risk allele and/or aC2 risk allele and/or a CFB risk allele and/or a C3 risk allele. In someembodiments, the patient is determined to carry 1, 2, 3, 4, 5, 6, 7, 8,9, 10, etc. AMD risk alleles. In some embodiments, presence of a riskallele in a patient comprises determining the identity of the nucleotideat the polymorphism from nucleic acid provided from a sample from apatient. In some embodiments, the nucleic acid sample comprises DNA. Insome embodiments, the nucleic acid sample comprises RNA. In someembodiments, the nucleic acid sample is amplified. In some embodiments,the nucleic acid sample is amplified by a polymerase chain reaction. Insome embodiments, the polymorphism is detected by polymerase chainreaction or sequencing. In some embodiments, the polymorphism isdetected by amplification of a target region containing at least onepolymorphism, and hybridization with at least one sequence-specificoligonucleotide that hybridizes under stringent conditions to at leastone polymorphism and detecting the hybridization. In some embodiments,the polymorphism is detected by a technique selected from the groupconsisting of scanning probe and nanopore DNA sequencing,pyrosequencing, Denaturing Gradient Gel Electrophoresis (DGGE), TemporalTemperature Gradient Electrophoresis (TTGE), Zn(II)-cyclenpolyacrylamide gel electrophoresis, homogeneous fluorescent PCR-basedsingle nucleotide polymorphism analysis, phosphate-affinitypolyacrylamide gel electrophoresis, high-throughput SNP genotypingplatforms, molecular beacons, 5′ nuclease reaction, Taqman assay,MassArray (single base primer extension coupled with matrix-assistedlaser desorption/ionization time-of-flight mass spectrometry), tritylmass tags, genotyping platforms (such as the Invader Assay®), singlebase primer extension (SBE) assays, PCR amplification (e.g. PCRamplification on magnetic nanoparticles (MNPs), restriction enzymeanalysis of PCR products (RFLP methods), allele-specific PCR, multipleprimer extension (MPEX), and isothermal smart amplification. In someembodiments, the sample is any biological sample from which genomic DNAmay be isolated, for example, but not to be limited to a tissue sample,a sample of saliva, a cheek swab sample, blood, or other biologicalfluids that contain genomic DNA. In some embodiments, the blood sampleincludes whole-blood, blood-derived cells, plasma, serum andcombinations thereof. In some embodiments, the identity of thenucleotide at the polymorphism in a patient is determined viagenotyping. In some embodiments the genotyping is performed by PCRanalysis, sequence analysis or LCR analysis. In some embodiments, thepatient is identified as having an increased risk for AMD progressionand is more likely to benefit from treatment comprising an anti-factor Dantibody, or antigen-binding fragment thereof when at least one allelecomprising a nucleotide selected from the group consisting of a Gnucleotide at the SNP rs4698775 is present, a G nucleotide at the SNPrs17440077 is present, an A nucleotide at the SNP rs10737680 is present,a G nucleotide at the SNP rs1329428 is present, a G nucleotide at theSNP rs429608 is present or the G nucleotide at the SNP rs2230199 ispresent. The patient is identified as being at increased risk of AMDprogression if the patient has one or two copies of the G allele atrs4698775 or rs17440077 associated with CFI, or equivalent allelethereof, at rs1329428 associated with CFH, or equivalent allele thereof,at rs429608 associated with C2/CFB, or equivalent allele thereof, or atrs2230199 associated with C3, or equivalent allele thereof or one or twocopies of the A allele at rs10737680 associated with CFH, or equivalentallele thereof. In one embodiment, the study eye in the patient has aBCVA between 20/25 and 20/400. In one embodiment, the study eye in thepatient has a BCVA between 20/25 and 20/100. In one embodiment, thestudy eye in the patient has a BCVA between 20/50 and 20/400. In oneembodiment; the study eye in the patient has a BCVA between 20/50 and20/100. In one embodiment, the study eye in the patient has a BCVAbetter than 20/25 or worse than 20/400. In one embodiment, the BCVA wasdetermined using ETDRS charts, In some embodiments, the antibody orantigen-binding fragment thereof is administered intravitreally. In someembodiments, the age-related macular degeneration is dry AMD. In someembodiments, the dry AMD is advanced dry AMD. In some embodiments, theadvanced dry AMD is geographic atrophy. In some embodiments, theage-related macular degeneration is early AMD or intermediate AMD. Insome embodiments, the patient with early AMD or intermediate AMD has areduction or delay in appearance of clinical signs (e.g. may includemeasuring the number and size of drusen (for early and intermediate AMD)and monitoring hypo- and hyperpigmentation associated with drusen (forintermediate AMD)). In some embodiments, the methods further compriseadministering a second medicament to the subject. In some embodiments,the second medicament is VEGF inhibitor.

Yet another embodiment of the invention provides methods for determiningthe likelihood that a AMD patient will benefit from treatment with ananti-factor D antibody, or antigen-binding fragment thereof, the methodcomprising determining genotype of the patient, wherein a patient whocarries a risk allele, is identified as a patient who has an increasedrisk of AMD progression and is more likely to respond to treatment withan anti-factor D antibody, or antigen-binding fragment thereof. In someembodiments, the antibody is lampalizumab. In some embodiments, the riskallele is the minor allele of a selected SNP. In some embodiments, therisk allele is the major allele of a selected SNP. In some embodiments,the risk allele (e.g. AMD-associated polymorphism) may be a CFI riskallele, a CFH risk allele, a C2 risk allele, a CFB risk allele and/or aC3 risk allele. In some embodiments, the risk allele is a CFI riskallele. In some embodiments, the CFI risk allele is the rs4698775:Gallele, or equivalent allele thereof or comprises a G at the selectedSNP rs4698775, or comprises an alternate SNP in linkage disequilibriumto rs4698775. In some embodiments, the alternate SNP comprises a minorallele or the allele which resides on the same haplotype of the riskallele of the selected SNP rs4698775. In some embodiments, the CFI riskallele is the rs17440077:G allele, or equivalent allele thereof orcomprises a G at the selected SNP rs17440077, or comprises an alternateSNP in linkage disequilibrium to rs17440077. In some embodiments, thealternate SNP comprises a minor allele or the allele which resides onthe same haplotype of the risk allele of the selected SNP rs17440077. Insome embodiments, the CFH risk allele is the rs10737680:A allele, orequivalent allele thereof, or comprises an A at the selected SNPrs10737680, or comprises an alternate SNP in linkage disequilibrium tors10737680. In some embodiments, the alternate SNP comprises a minorallele or the allele which resides on the same haplotype of the riskallele of the selected SNP rs10737680. In some embodiments, the CFH riskallele is the rs1329428:G allele, or equivalent allele thereof, orcomprises an G at the selected SNP rs1329428, or comprises an alternateSNP in linkage disequilibrium to rs1329428. In some embodiments, thealternate SNP comprises a minor allele or the allele which resides onthe same haplotype of the risk allele of the selected SNP rs1329428. Insome embodiments, the C2 risk allele is the rs429608:G allele, orequivalent allele thereof, or comprises a G at the selected SNPrs429608, or comprises an alternate SNP in linkage disequilibrium tors429608. In some embodiments, the alternate SNP comprises a minorallele or the allele which resides on the same haplotype of the riskallele of the selected SNP rs429608. In some embodiments, the CFB alleleis the rs429608:G allele, or equivalent allele thereof, or comprises a Gat the selected SNP rs429608, or comprises an alternate SNP in linkagedisequilibrium to rs429608. In some embodiments, the alternate SNPcomprises a minor allele or the allele which resides on the samehaplotype of the risk allele of the selected SNP rs429608. In someembodiments, the C3 risk allele is the rs2230199:G allele, or equivalentallele thereof, or comprises a G at the selected SNP rs2230199 orcomprises an alternate SNP in linkage disequilibrium to rs2230199. Insome embodiments, the alternate SNP comprises a minor allele or theallele which resides on the same haplotype of the risk allele of theselected SNP rs2230199. In some embodiments, the linkage disequilibriumis a D′ measure or an r² measure. In some embodiments, the D′ measurebetween the selected SNP and the alternate SNP is ≥0.60. In someembodiments, the D′ measure between the selected SNP and the alternateSNP is ≥0.70, 0.80 or 0.90. In some embodiments, the D′ measure betweenthe selected SNP and the alternate SNP is 1.0. In some embodiments, ther² measure between the selected SNP and the alternate SNP is ≥0.60. Insome embodiments the r² measure between the selected SNP and thealternate SNP is ≥0.70, 0.80 or 0.90. In some embodiments, the r²measure between the selected SNP and the alternate SNP is 1.0. In someembodiments, the alternate SNP is a SNP designated in Tables 4-7. Insome embodiments, the SNP rs4698775 is located at position 110590479 onhuman chromosome 4 (Genome Reference Consortium GRCh37; UCSC Genome HG19Assembly; February 2009) and the G allele changes the nucleotidesequence from T to G. In some embodiments, the SNP rs17440077 is locatedat position 110537567 on human chromosome 4 (Genome Reference ConsortiumGRCh37; UCSC Genome HG19 Assembly; February 2009) and the G allelechanges the nucleotide sequence from A to G. In some embodiments, theSNP rs10737680 is located at position 196679455 on human chromosome 1(Genome Reference Consortium GRCh37; UCSC Genome HG19 Assembly; February2009) and the A allele changes the nucleotide sequence form C to A. Insome embodiments, the SNP rs1329428 is located at position 196702810 onhuman chromosome 1 (Genome Reference Consortium GRCh37; UCSC Genome HG19Assembly; February 2009) and the G allele changes the nucleotidesequence from A to G. In some embodiments, the SNP rs429608 is locatedat position 31930462 on human chromosome 6 (Genome Reference ConsortiumGRCh37; UCSC Genome HG19 Assembly; February 2009) and the G allelechanges the nucleotide sequence from A to G. In some embodiments, theSNP rs2230199 is located at position 6718387 on human chromosome 19(Genome Reference Consortium GRCh37; UCSC Genome HG19 Assembly; February2009) and the G allele changes the nucleotide sequence from C to G andchanges the encoded amino acid from arginine to glycine. In someembodiments, the alternate SNP is located on human chromosome 4 betweenSEC24B gene and EGF gene (for rs4698775) (Genome Reference ConsortiumGRCh37; UCSC Genome HG19 Assembly; February 2009), human chromosome 4between SEC24B gene and EGF gene (Genome Reference Consortium GRCh37;UCSC Genome HG19 Assembly; February 2009) (for rs17440077), humanchromosome 1 between KCNT2 gene and LHX9 gene (Genome ReferenceConsortium GRCh37; UCSC Genome HG19 Assembly; February 2009) (forrs10737680), human chromosome 1 between KCNT2 gene and LHX9 gene (GenomeReference Consortium GRCh37; UCSC Genome HG19 Assembly; February 2009)(for rs1329428), human chromosome 6 between SLC44A4 gene and TNXB gene(Genome Reference Consortium GRCh37; UCSC Genome HG19 Assembly; February2009) (for rs429608), human chromosome 19 between TNFSF14 gene and VAV1gene (Genome Reference Consortium GRCh37; UCSC Genome HG19 Assembly;February 2009) (for rs2230199). In some embodiments, the alternate SNPis located within 500,000 base pairs upstream and downstream of theselected SNP In some embodiments, the patient is determined to carry aCFI risk allele and/or a CFH risk allele and/or a C2 risk allele and/ora CFB risk allele and/or a C3 risk allele. In some embodiments, thepatient is determined to carry 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc. AMDrisk alleles. In some embodiments, presence of a risk allele in apatient comprises determining the identity of the nucleotide at thepolymorphism from nucleic acid provided from a sample from a patient. Insome embodiments, the nucleic acid sample comprises DNA. In someembodiments, the nucleic acid sample comprises RNA. In some embodiments,the nucleic acid sample is amplified. In some embodiments, the nucleicacid sample is amplified by a polymerase chain reaction. In someembodiments, the polymorphism is detected by polymerase chain reactionor sequencing. In some embodiments, the polymorphism is detected byamplification of a target region containing at least one polymorphism,and hybridization with at least one sequence-specific oligonucleotidethat hybridizes under stringent conditions to at least one polymorphismand detecting the hybridization. In some embodiments, the polymorphismis detected by a technique selected from the group consisting ofscanning probe and nanopore DNA sequencing, pyrosequencing, DenaturingGradient Gel Electrophoresis (DGGE), Temporal Temperature GradientElectrophoresis (TTGE), Zn(II)-cyclen polyacrylamide gelelectrophoresis, homogeneous fluorescent PCR-based single nucleotidepolymorphism analysis, phosphate-affinity polyacrylamide gelelectrophoresis, high-throughput SNP genotyping platforms, molecularbeacons, 5′ nuclease reaction, Taqman assay, MassArray (single baseprimer extension coupled with matrix-assisted laserdesorption/ionization time-of-flight mass spectrometry), trityl masstags, genotyping platforms (such as the Invader Assay®), single baseprimer extension (SBE) assays, PCR amplification (e.g. PCR amplificationon magnetic nanoparticles (MNPs), restriction enzyme analysis of PCRproducts (RFLP methods), allele-specific PCR, multiple primer extension(MPEX), and isothermal smart amplification. In some embodiments, thesample is any biological sample from which genomic DNA may be isolated,for example, but not to be limited to a tissue sample, a sample ofsaliva, a cheek swab sample, blood, or other biological fluids thatcontain genomic DNA. In some embodiments, the identity of the nucleotideat the polymorphism in a patient is determined via genotyping. In someembodiments the genotyping is performed by PCR analysis, sequenceanalysis or LCR analysis. In some embodiments, the patient is identifiedas having an increased risk for AMD progression and is more likely tobenefit from treatment comprising an anti-factor D antibody, orantigen-binding fragment thereof when at least one allele comprising anucleotide selected from the group consisting of a G nucleotide at theSNP rs4698775 is present, a G nucleotide at the SNP rs17440077 ispresent, a G nucleotide at the SNP rs10737680 is present, a G nucleotideat the SNP rs1329428 is present, a G nucleotide at the SNP rs429608 ispresent or the G nucleotide at the SNP rs2230199 is present. The patientis identified as being at increased risk of AMD progression if thepatient has one or two copies of the G allele at rs4698775 or rs17440077associated with CFI, or equivalent allele thereof, at rs1329428associated with CFH, or equivalent allele thereof, at rs429608associated with C2/CFB, or equivalent allele thereof, or at rs2230199associated with C3, or equivalent allele thereof or one or two copies ofthe A allele at rs10737680 associated with CFH, or equivalent allelethereof. In one embodiment, the study eye in the patient has a BCVAbetween 20/25 and 20/400. In one embodiment, the study eye in thepatient has a BCVA between 20/25 and 20/100. In one embodiment, thestudy eye in the patient has a BCVA between 20/50 and 20/400. In oneembodiment, the study eye in the patient has a BCVA between 20/50 and20/100. In one embodiment, the study eye in the patient has a BCVAbetter than 20/25 or worse than 20/400. In one embodiment, the BCVA wasdetermined using ETDRS charts. In some embodiments, the antibody orantigen-binding fragment thereof is administered intravitreally. In someembodiments, the age-related macular degeneration is dry AMD. In someembodiments, the dry AMD is advanced dry AMD. In some embodiments, theadvanced dry AMD is geographic atrophy. In some embodiments, theage-related macular degeneration is early AMD or intermediate AMD. Insome embodiments, the patient with early AMD or intermediate AMD has areduction or delay in appearance of clinical signs (e.g. may includemeasuring the number and size of drusen (for early and intermediate AMD)and monitoring hypo- and hyperpigmentation associated with drusen (forintermediate AMD)). In some embodiments, the methods further compriseadministering a second medicament to the subject. In some embodiments,the second medicament is VEGF inhibitor.

Even another embodiment of the invention provides methods of treatingdegenerative disease (e.g. AMD) in a patient, the method comprisingadministering an effective amount of an anti-factor D antibody orantigen-binding fragment thereof to a patient diagnosed with adegenerative disease, wherein the patient has decreased progression ofAMD following treatment compared to a control. In some embodiments, theantibody is lampalizumab. In one embodiment, the degenerative disease isan ocular degenerative disease. In one embodiment, the oculardegenerative disease is age-related macular degeneration. In oneembodiment, the study eye in the patient has a BCVA between 20/25 and20/400. In one embodiment, the study eye in the patient has a BCVAbetween 20/25 and 20/100. In one embodiment, the study eye in thepatient has a BCVA between 20/50 and 20/400. In one embodiment, thestudy eye in the patient has a BCVA between 20/50 and 20/100. In oneembodiment, the study eye in the patient has a BCVA better than 20/25 orworse than 20/400. In one embodiment, the BCVA was determined usingETDRS charts. In some embodiments, the antibody or antigen-bindingfragment thereof is administered intravitreally. In some embodiments,the age-related macular degeneration is dry AMD. In some embodiments,the dry AMD is advanced dry AMD. In some embodiments, the advanced dryAMD is geographic atrophy. In some embodiments, the patient has areduced mean change in geographic atrophy (GA) area followingadministration of the antibody as compared to control patients that didnot receive the antibody treatment. In some embodiments, the mean changein GA area is determined by measuring the GA area by standard imagingmethods (e.g. fundus autofluorescence (FAF) or color fundus photography(CFP). In some embodiments, the age-related macular degeneration isearly AMD or intermediate AMD. In some embodiments, the patient withearly AMD or intermediate AMD has a reduction or delay in appearance ofclinical signs (e.g. may include measuring the number and size of drusen(for early and intermediate AMD) and monitoring hypo- andhyperpigmentation associated with drusen (for intermediate AMD)). Insome embodiments, the methods further comprise administering a secondmedicament to the subject. In some embodiments, the second medicament isVEGF inhibitor.

Even a further embodiment of the invention provides methods ofidentifying an degenerative disease patient (e.g., AMD patient) who maybenefit from treatment with an anti-factor D antibody, orantigen-binding fragment thereof, the method comprising determining thebaseline GA area of the patient, wherein a patient who has a baseline GAarea that requires clinical intervention is identified as a patient whomay benefit from treatment with an anti-factor D antibody. In oneembodiment, the degenerative disease is an ocular degenerative disease.In one embodiment, the ocular degenerative disease is age-relatedmacular degeneration. In some embodiments, the antibody is lampalizumab.In one embodiment, the study eye in the patient has a BCVA between 20/25and 20/400. In one embodiment, the study eye in the patient has a BC VAbetween 20/25 and 20/100. In one embodiment, the study eye in thepatient has a BC VA between 20/50 and 20/400. In one embodiment, thestudy eye in the patient has a BCVA between 20/50 and 20/100. In oneembodiment, the study eye in the patient has a BCVA better than 20/25 orworse than 20/400. In one embodiment, the BCVA was determined usingETDRS charts. In some embodiments, the antibody or antigen-bindingfragment thereof is administered intravitreally. In some embodiments,the age-related macular degeneration is dry AMD. In some embodiments,the dry AMD is advanced dry AMD. In some embodiments, the advanced dryAMD is geographic atrophy. In some embodiments, the patient has areduced mean change in geographic atrophy (GA) area followingadministration of the antibody as compared to the control patients thatdid not receive the antibody treatment. In some embodiments, the meanchange in GA area is determined by measuring the GA area by standardimaging methods (e.g. fundus autofluorescence (FAF) or color fundusphotography (CFB). In some embodiments, the age-related maculardegeneration is early AMD or intermediate AMD. In some embodiments, thepatient with early AMD or intermediate AMD has a reduction or delay inappearance of clinical signs (e.g. may include measuring the number andsize of drusen (for early and intermediate AMD) and monitoring hypo- andhyperpigmentation associated with drusen (for intermediate AMD)). Insome embodiments, the methods further comprise administering a secondmedicament to the subject. In some embodiments, the second medicament isVEGF inhibitor.

In some embodiments, the complement inhibitor in the methods describedherein is an anti-anti-factor D antibody, or antigen-binding fragmentthereof. In some embodiments, the antibody specifically binds factor D.In some embodiments, the antibody comprises a light chain comprisingHVR-L1 comprising the amino acid sequence ITSTDIDDDMN (SEQ ID NO:1),HVR-L2 comprising the amino acid sequence GGNTLRP (SEQ ID NO:2), andHVR-L3 comprising the amino acid sequence LQSDSLPYT (SEQ ID NO: 3);and/or a heavy chain comprising HVR-H1 comprising the amino acidsequence GYTFTNYGMN (SEQ ID NO: 4), HVR-H2 comprising the amino acidsequence WINTYTGETTYADDFKG (SEQ ID NO:5), and HVR-H3 comprising theamino acid sequence EGGVNN (SEQ ID NO:6). In some embodiments, theantibody comprises a heavy chain variable region sequence of at least95% sequence identity to the amino acid sequence of SEQ ID NO:7; and/ora light chain variable region sequence of at least 95% sequence identityto the amino acid sequence of SEQ ID NO:8. In some embodiments, theantibody comprises a heavy chain variable region comprising the aminoacid sequence of SEQ ID NO:7; and/or a light chain variable regioncomprising the amino acid sequence of SEQ ID NO:8. In some embodiments,the antibody is lampalizumab having CAS registration number1278466-20-8. In some embodiments, the anti-factor D antibody may be amonoclonal antibody, antibody fragment, chimeric antibody, humanizedantibody, single-chain antibody or antibody that competitively inhibitsthe binding of an anti-factor D antibody to its respective antigenicepitope. In one embodiment, the anti-factor D antibody competitivelyinhibits the binding of the anti-factor D antibody comprising a lightchain comprising HVR-L1 comprising the amino acid sequence ITSTDIDDDMN(SEQ ID NO:1), HVR-L2 comprising the amino acid sequence GGNTLRP (SEQ IDNO:2), and HVR-L3 comprising the amino acid sequence LQSDSLPYT (SEQ IDNO: 3); and/or a heavy chain comprising HVR-H1 comprising the amino acidsequence GYTFTNYGMN (SEQ ID NO: 4), HVR-H2 comprising the amino acidsequence WINTYTGETTYADDFKG (SEQ ID NO:5), and HVR-H3 comprising theamino acid sequence EGGVNN (SEQ ID NO:6) to its respective antigenicepitope. In one embodiment, the anti-factor D antibody competitivelyinhibits the binding of the antibody comprising a heavy chain variableregion sequence of at least 95% sequence identity to the amino acidsequence of SEQ ID NO:7; and/or a light chain variable region sequenceof at least 95% sequence identity to the amino acid sequence of SEQ IDNO:8 to its respective antigenic epitope. In one embodiment, theanti-factor D antibody competitively inhibits the binding of theantibody comprising a heavy chain sequence of at least 95% sequenceidentity to the amino acid sequence of SEQ ID NO:15; and/or a lightchain sequence of at least 95% sequence identity to the amino acidsequence of SEQ ID NO:16 to its respective antigenic epitope. In oneembodiment, the anti-factor D antibody competitively inhibits thebinding of the antibody comprising a heavy chain variable regioncomprising the amino acid sequence of SEQ ID NO:7; and/or a light chainvariable region comprising the amino acid sequence of SEQ ID NO:8 to itsrespective antigenic epitope. In one embodiment, the anti-factor Dantibody competitively inhibits the binding of the antibody comprising aheavy chain comprising the amino acid sequence of SEQ ID NO:15; and/or alight chain comprising the amino acid sequence of SEQ ID NO:16 to itsrespective antigenic epitope. In one embodiment, the anti-factor Dantibody competitively inhibits the binding of lampalizumab having CASregistration number 1278466-20-8 to its respective antigenic epitope. Insome embodiments, the anti-factor D antibody binds to the same epitopeon factor D bound by another factor D antibody. In one embodiment, theanti-factor D antibody binds to the same epitope on factor D bound bythe anti-factor D antibody comprising a light chain comprising HVR-L1comprising the amino acid sequence ITSTDIDDDMN (SEQ ID NO:1), HVR-L2comprising the amino acid sequence GGNTLRP (SEQ ID NO:2), and HVR-L3comprising the amino acid sequence LQSDSLPYT (SEQ ID NO: 3); and/or aheavy chain comprising HVR-H1 comprising the amino acid sequenceGYTFTNYGMN (SEQ ID NO: 4), HVR-H2 comprising the amino acid sequenceWINTYTGETTYADDFKG (SEQ ID NO:5), and HVR-H3 comprising the amino acidsequence EGGVNN (SEQ ID NO:6). In one embodiment, the anti-factor Dantibody binds to the same epitope on factor D bound by the antibodycomprising a heavy chain variable region sequence of at least 95%sequence identity to the amino acid sequence of SEQ ID NO:7; and/or alight chain variable region sequence of at least 95% sequence identityto the amino acid sequence of SEQ ID NO:8. In one embodiment, theanti-factor D antibody binds to the same epitope on factor D bound bythe antibody comprising a heavy chain sequence of at least 95% sequenceidentity to the amino acid sequence of SEQ ID NO:15; and/or a lightchain sequence of at least 95% sequence identity to the amino acidsequence of SEQ ID NO:16. In one embodiment, the anti-factor D antibodybinds to the same epitope on factor D bound by the antibody comprising aheavy chain variable region comprising the amino acid sequence of SEQ IDNO:7; and/or a light chain variable region comprising the amino acidsequence of SEQ ID NO:8. In one embodiment, the anti-factor D antibodybinds to the same epitope on factor D bound by the antibody comprising aheavy chain comprising the amino acid sequence of SEQ ID NO:15; and/or alight chain comprising the amino acid sequence of SEQ ID NO:16. In oneembodiment, the anti-factor D antibody binds to the same epitope onfactor D bound by lampalizumab having CAS registration number1278466-20-8.

In some embodiments, the anti-factor D antibody, or antigen-bindingfragment thereof is administered intraocularly or intravitreally. Insome embodiments, the antibody is administered at a flat dose of 10 mg.In some embodiments, the antibody is administered at a flat dose of 10mg monthly or 10 mg every other month. In some embodiments, the antibodyis administered intravitreally at a flat dose of 10 mg monthly or 10 mgevery other month. In some embodiments, alternative formulations ormodes of drug delivery of the anti-factor D antibody or antigen bindingfragment may involve lower or higher doses than 10 mg. In someembodiments, the anti-factor D antibody, or antigen-binding fragmentthereof, is administered at a dose lower than 10 mg if administered viaa long-acting delivery (LAD) device. For example, the anti-factor Dantibody, or antigen-binding fragment thereof is administered at a doseof 9, 8, 7, 6, 5, 4, 3, 2, 1 mg. In some embodiments, the anti-factor Dantibody, or antigen-binding fragment thereof, is administered at a dosegreater than 10 mg if administered intravitreally. For example, theanti-factor D antibody, or antigen-binding fragment thereof, isadministered at a dose of 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 mg.

In some embodiments, the administration of the antibody is effective inone or more of the following: (1) reduction in GA area, (2) reduction ofvision loss. In some embodiments, the methods described herein furthercomprise administering a second medicament to the patient. In someembodiments, the second medicament is a VEGF inhibitor. In someembodiments, the second medicament is a standard of care for AMD.

In another aspect, the invention provides a therapeutic regimen for thetreatment of a patient carrying a risk allele and in need thereofcomprising the administration of a factor D inhibitor. In someembodiments, the complement inhibitor is an anti-factor D antibody, orantigen-binding fragment thereof. In some embodiments, the antibody isadministered at a flat dose of 5-30 mg. In some embodiments, theantibody is administered at a flat dose of 5-15 mg monthly or 10-30 mgevery other month. In some embodiments, the antibody is administeredintraocularly or intravitreally. In some embodiments, the antibody isadministered intravitreally at a flat dose of 5 mg or 15 mg monthly. Insome embodiments, the antibody comprises a light chain comprising HVR-L1comprising the amino acid sequence ITSTDIDDDMN (SEQ ID NO:1), HVR-L2comprising the amino acid sequence GGNTLRP (SEQ ID NO:2), and HVR-L3comprising the amino acid sequence LQSDSLPYT (SEQ ID NO: 3); and/or aheavy chain comprising HVR-H1 comprising the amino acid sequenceGYTFTNYGMN (SEQ ID NO: 4), HVR-H2 comprising the amino acid sequenceWINTYTGETTYADDFKG (SEQ ID NO:5), and HVR-H3 comprising the amino acidsequence EGGVNN (SEQ ID NO:6). In some embodiments, the antibodycomprises a heavy chain variable region sequence of at least 95%sequence identity to the amino acid sequence of SEQ ID NO:7; and/or alight chain variable region sequence of at least 95% sequence identityto the amino acid sequence of SEQ ID NO:8. In some embodiments, theantibody comprises a heavy chain variable region comprising the aminoacid sequence of SEQ ID NO:7

(EVQLVQSGPELKKPGASVKVSCKAS GYTFTNYGMN WVRQAPGQGLEWM G WINT YTGETTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCE R EGGVNNWGQGTLVTVSS; HVRs are underlined and in bold);and/or a light chain variable region comprising the amino acid sequenceof SEQ ID NO:8

(DIQVTQSPSSLSASVGDRVTITC ITSTDIDDDMN WYQQKPGKVPKLLI S GGNTLRPGVPSRFSGSGSGTDFTLTISSLQPEDVATYYC LQSDSLPYTFGQGTKVEIK; HVRs are underlined and in bold);In some embodiments, the antibody is lampalizumab having CASregistration number 1278466-20-8. In some embodiments, the anti-factor Dantibody may be a monoclonal antibody, antibody fragment, chimericantibody, humanized antibody, single-chain antibody or antibody thatcompetitively inhibits the binding of an anti-factor D antibody to itsrespective antigenic epitope. In one embodiment, the anti-factor Dantibody competitively inhibits the binding of the anti-factor Dantibody comprising a light chain comprising HVR-L1 comprising the aminoacid sequence ITSTDIDDDMN (SEQ ID NO:1), HVR-L2 comprising the aminoacid sequence GGNTLRP (SEQ ID NO:2), and HVR-L3 comprising the aminoacid sequence LQSDSLPYT (SEQ ID NO: 3); and/or a heavy chain comprisingHVR-H1 comprising the amino acid sequence GYTFTNYGMN (SEQ ID NO: 4),HVR-H2 comprising the amino acid sequence WINTYTGETTYADDFKG (SEQ IDNO:5), and HVR-H3 comprising the amino acid sequence EGGVNN (SEQ IDNO:6) to its respective antigenic epitope. In one embodiment, theanti-factor D antibody competitively inhibits the binding of theantibody comprising a heavy chain variable region sequence of at least95% sequence identity to the amino acid sequence of SEQ ID NO:7; and/ora light chain variable region sequence of at least 95% sequence identityto the amino acid sequence of SEQ ID NO:8 to its respective antigenicepitope. In one embodiment, the anti-factor D antibody competitivelyinhibits the binding of the antibody comprising a heavy chain sequenceof at least 95% sequence identity to the amino acid sequence of SEQ IDNO:15; and/or a light chain sequence of at least 95% sequence identityto the amino acid sequence of SEQ ID NO:16 to its respective antigenicepitope. In one embodiment, the anti-factor D antibody competitivelyinhibits the binding of the antibody comprising a heavy chain variableregion comprising the amino acid sequence of SEQ ID NO:7; and/or a lightchain variable region comprising the amino acid sequence of SEQ ID NO:8to its respective antigenic epitope. In one embodiment, the anti-factorD antibody competitively inhibits the binding of the antibody comprisinga heavy chain comprising the amino acid sequence of SEQ ID NO:15; and/ora light chain comprising the amino acid sequence of SEQ ID NO:16 to itsrespective antigenic epitope. In one embodiment, the anti-factor Dantibody competitively inhibits the binding of lampalizumab having CASregistration number 1278466-20-8 to its respective antigenic epitope. Insome embodiments, the anti-factor D antibody binds to the same epitopeon factor D bound by another factor D antibody. In one embodiment, theanti-factor D antibody binds to the same epitope on factor D bound bythe anti-factor D antibody comprising a light chain comprising HVR-L1comprising the amino acid sequence ITSTDIDDDMN (SEQ ID NO:1), HVR-L2comprising the amino acid sequence GGNTLRP (SEQ ID NO:2), and HVR-L3comprising the amino acid sequence LQSDSLPYT (SEQ ID NO: 3); and/or aheavy chain comprising HVR-H1 comprising the amino acid sequenceGYTFTNYGMN (SEQ ID NO: 4), HVR-H2 comprising the amino acid sequenceWINTYTGETTYADDFKG (SEQ ID NO:5), and HVR-H3 comprising the amino acidsequence EGGVNN (SEQ ID NO:6). In one embodiment, the anti-factor Dantibody binds to the same epitope on factor D bound by the antibodycomprising a heavy chain variable region sequence of at least 95%sequence identity to the amino acid sequence of SEQ ID NO:7; and/or alight chain variable region sequence of at least 95% sequence identityto the amino acid sequence of SEQ ID NO:8. In one embodiment, theanti-factor D antibody binds to the same epitope on factor D bound bythe antibody comprising a heavy chain sequence of at least 95% sequenceidentity to the amino acid sequence of SEQ ID NO:15; and/or a lightchain sequence of at least 95% sequence identity to the amino acidsequence of SEQ ID NO:16. In one embodiment, the anti-factor D antibodybinds to the same epitope on factor D bound by the antibody comprising aheavy chain variable region comprising the amino acid sequence of SEQ IDNO:7; and/or a light chain variable region comprising the amino acidsequence of SEQ ID NO:8. In one embodiment, the anti-factor D antibodybinds to the same epitope on factor D bound by the antibody comprising aheavy chain comprising the amino acid sequence of SEQ ID NO:15; and/or alight chain comprising the amino acid sequence of SEQ ID NO:16. In oneembodiment, the anti-factor D antibody binds to the same epitope onfactor D bound by lampalizumab having CAS registration number1278466-20-8.

In another aspect, the invention provides a method of identifying an AMDpatient who may benefit from an factor D inhibitor treatment, the methodcomprising determining the genotype from a sample from the patient,wherein a patient who carries the risk allele as measured by genotypeassay is identified as a patient who may benefit from the factor Dinhibitor treatment. In another aspect, the invention provides a methodof predicting responsiveness of an AMD patient to a factor D inhibitortreatment, the method comprising determining the genotype from a samplefrom the patient, wherein a patient who carries a risk allele isidentified as a patient who is likely to respond to the factor Dinhibitor treatment. In some embodiments, the genotype assay isperformed using a SNP array, Taqman (Hui et al., Current Protocol inHuman Genetics, Supp 56: 2.10.1-2.10.8 (2008)), fluorescencepolarization, Sequenom or other methods for analysis of SNPs asdescribed herein. In some embodiments, the genotype assay utilizes PCRor sequencing.

In another aspect, the invention provides a method of treating adegenerative disease comprising administering an anti-factor D antibody,or antigen-binding fragment thereof, comprising HVRH1, HVRH2, HVRH3,HVRL1, HVRL2, HVRL3, and HVRL3, wherein the respective HVRs have theamino acid sequence of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ IDNO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 to a patient suffering from adegenerative disease in a 10 mg dose every month. In one embodiment, thedegenerative disease is an ocular degenerative disease. In oneembodiment, the ocular degenerative disease is age related maculardegeneration. In one embodiment, the age related macular degeneration isearly, intermediate or advanced AMD. In one embodiment, the advanced AMDis geographic atrophy. In one embodiment, a second medicament isadministered. In one embodiment, the second medicament is a VEGFinhibitor. In one embodiment, the VEGF inhibitor is ranibizumab. In oneembodiment, the anti-factor D antibody, or antigen binding fragmentthereof, is an antibody or antigen binding fragment thereof comprising aVH comprising SEQ ID NO: 7 and a VL comprising SEQ ID NO: 8. In oneembodiment, the treatment results in greater than 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 2.6, 27, 28, 29,30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47,48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65,66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83,84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100%reduction of change in GA area from baseline GA area. In one embodiment,the treatment results in greater than 80% reduction of change in GA areafrom baseline GA area. In one embodiment, the treatment results ingreater than 75% reduction of change in GA area from baseline GA area.In one embodiment, the treatment results in greater than 70% reductionof change in GA area from baseline GA area. In one embodiment, thetreatment results in greater than 65% reduction of change in GA areafrom baseline GA area. In one embodiment, the treatment results ingreater than 60% reduction of change in GA area from baseline GA area.In one embodiment, the treatment results in greater than 55% reductionof change in GA area from baseline GA area. In one embodiment, thetreatment results in greater than 50% reduction of change in GA areafrom baseline GA area. In one embodiment, the treatment results ingreater than 45% reduction of change in GA area from baseline GA area.In one embodiment, the treatment results in greater than 40% reductionof change in GA area from baseline GA area. In one embodiment, thetreatment results in greater than 35% reduction of change in GA areafrom baseline GA area. In one embodiment, the treatment results ingreater than 30% reduction of change in GA area from baseline GA area.In one embodiment, the treatment results in greater than 25% reductionof change in GA area from baseline GA area. In one embodiment, thetreatment results in greater than 20% reduction of change in GA areafrom baseline GA area. In one embodiment, the treatment results ingreater than 15% reduction of change in GA area from baseline GA area.In one embodiment, the treatment results in greater than 10% reductionof change in GA area from baseline GA area. In one embodiment, thetreatment results in greater than 5% reduction of change in GA area frombaseline GA area. In one embodiment, the patient has geographic atrophysecondary to AMD. In one embodiment, the study eye in the patient has aBCVA between 20/25 and 20/400. In one embodiment, the study eye in thepatient has a BCVA between 20/25 and 20/100. In one embodiment, thestudy eye in the patient has a BCVA between 20/50 and 20/400. In oneembodiment, the study eye in the patient has a BCVA between 20/50 and20/100. In one embodiment, the study eye in the patient has a BCVAbetter than 20/25 or worse than 20/400. In one embodiment, the BCVA wasdetermined using ETDRS charts. In one embodiment, the patient has notreceived any previous intravitreal treatment, retinal surgery or otherretinal therapeutic procedures in the study eye.

In one aspect, the invention provides a kit for genotyping in abiological sample from a degenerative disease patient, wherein the kitcomprises oligonucleotides for polymerase chain reaction or sequencingfor detection of a risk allele. In another aspect, the inventionprovides a kit for determining the presence of at least one degenerativedisease-associated polymorphism in a biological sample, comprisingreagents and instructions for detecting the genotype of the biologicalsample for the presence of at least one degenerative disease-associatedpolymorphism, wherein the polymorphism is a risk allele selected fromthe group consisting of a CFI allele, a CFH allele, a C2 allele, a CFBallele, or a C3 allele. In one embodiment, the biological sample is ablood sample, saliva, cheek swab, tissue sample or a sample of bodilyfluids. In one embodiment, the biological sample is a nucleic acidsample. In one embodiment, the nucleic acid sample comprises DNA. In oneembodiment, the nucleic acid sample comprises RNA. In one embodiment,the nucleic acid sample is amplified. In one embodiment, the biologicalsample is obtained from a patient diagnosed with a degenerative disease,such as AMD, including early, intermediate and advanced AMD. In oneembodiment, the advanced AMD is GA. In one embodiment, the kit furthercomprises a package insert for determining whether a degenerativedisease patient is likely to respond to an anti-factor D antibody, orantigen binding fragment thereof. In one embodiment, the kit is used todetect the presence of a CFI risk allele, a CFH risk allele, a C2 riskallele, a CFB risk allele or a C3 risk allele. In one embodiment, thekit is used to detect the presence of one or two alleles of the Ggenotype at the SNP rs4698775, SNP rs17440077, SNP rs1329428, SNPrs429608 or SNP rs2230199 or two alleles of the A genotype at the SNPrs10737680. In one embodiment, the reagents of the kit comprise a set ofoligonucleotides specific for detecting a polymorphism in CFI, C2, CFB,C3 or CFH allele. The oligonucleotides according to the invention can bea forward primer and a reverse primer suitable for amplifying a regionof the CFI, C2, CFB, C3 or CFH gene comprising a polymorphism in CFI,C2, CFB, C3 or CFH respectively, selected from the group consisting ofthe G genotype at the SNP rs4698775, SNP rs17440077, SNP rs1329428, SNPrs429608 or SNP rs2230199 or the A genotype at the SNP rs10737680. Thekit can further comprises an oligonucleotide probe for detecting thepolymorphism. Oligonucleotides useful as primers and probes for theinvention included those listed in Table 9 as SEQ ID NOs:17-41. In oneaspect, the reagents of the kit comprise (i) a forward primer of SEQ IDNO:17 or 18 combined with a reverse primer of SEQ ID NO:19 or 20 and alabeled probe selected from SEQ ID NOs. 21-24; (ii) a forward primer ofSEQ ID NO:25 or 26 combined with a reverse primer of SEQ ID NO:27 or 28and a labeled probe selected from SEQ ID NOs. 29-33; or (iii) a forwardprimer of SEQ ID NO:34 or 35 combined with a reverse primer of SEQ IDNO:36 or 37 and a labeled probe selected from SEQ ID NOs. 38-41. In oneembodiment, the reagents of the kit combine primers and probes as listedin (i), (ii) and (iii) above.

In another aspect, the invention provides a kit for predicting whether apatient has an increased likelihood of benefiting from treatment with ananti-factor D antibody or antigen binding fragment thereof comprising afirst oligonucleotide and a second oligonucleotide specific for apolymorphism in CFI, C2, CFB, C3 or CFH. In one embodiment, said firstoligonucleotide and said second oligonucleotide may be used to amplify aregion of the CFI, C2, CFB, C3 or CFH gene comprising a polymorphism inCFI, C2, CFB, C3 or CFH respectively, selected from the group consistingof the G genotype at the SNP rs4698775, SNP rs17440077, SNP rs1329428,SNP rs429608 or SNP rs2230199 or the A genotype at the SNP rs10737680.In one embodiment, the anti-factor D antibody, or antigen-bindingfragment thereof, comprises HVRH1, HVRH2, HVRH3, HVRL1, HVRL2, HVRL3,and HVRL3, wherein the respective HVRs have the amino acid sequence ofSEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5 andSEQ ID NO: 6.

In one aspect of the invention, the anti-factor D antibody, orantigen-binding fragment thereof, comprises the variable heavy chain ofSEQ ID NO: 7 and/or the variable light chain of SEQ ID NO: 8.

In one aspect of the invention, the polymorphism is a CFI polymorphism.In one embodiment, the CFI polymorphism is present in combination withone or more additional polymorphisms selected from the group consistingof a CFH polymorphism, a C2 polymorphism, a C3 polymorphism or a CFBpolymorphism.

In one aspect, the invention provides the use of an agent thatspecifically binds to at least one degenerative disease-associatedpolymorphism wherein the polymorphism is a minor allele selected fromthe group consisting of a CFI risk allele, a CFH risk allele, a C2 riskallele, a CFB risk allele or a C3 risk allele for the manufacture of adiagnostic for diagnosing a degenerative disease. In one embodiment, theCFI allele is an equivalent allele thereof, the CFH allele is anequivalent allele thereof, the C2 allele is an equivalent allelethereof, the CFB allele is an equivalent allele thereof, or the C3allele is an equivalent allele thereof. In one embodiment, the CFIallele comprises a G at the single nucleotide polymorphism (SNP)rs4698775 or rs17440077, the CFH allele comprises an A at the singlenucleotide polymorphism (SNP) rs10737680 or a G at the single nucleotidepolymorphism (SNP) rs1329428, the C2 allele comprises a G at the singlenucleotide polymorphism (SNP) rs429608, the CFB allele comprises a G atthe single nucleotide polymorphism (SNP) rs429608, and the C3 allelecomprises a G at the single nucleotide polymorphism (SNP) rs2230199. Inone embodiment, at least one polymorphism is detected by a techniqueselected from the group consisting of scanning probe and nanopore DNAsequencing, pyrosequencing, Denaturing Gradient Gel Electrophoresis(DGGE), Temporal Temperature Gradient Electrophoresis (TTGE),Zn(II)-cyclen polyacrylamide gel electrophoresis, homogeneousfluorescent PCR-based single nucleotide polymorphism analysis,phosphate-affinity polyacrylamide gel electrophoresis, high-throughputSNP genotyping platforms, molecular beacons, 5′ nuclease reaction,Taqman assay, MassArray (single base primer extension coupled withmatrix-assisted laser desorption/ionization time-of-flight massspectrometry), trityl mass tags, genotyping platforms (such as theInvader Assay®), single base primer extension (SBE) assays, PCRamplification (e.g. PCR amplification on magnetic nanoparticles (MNPs),restriction enzyme analysis of PCR products (RFLP methods),allele-specific PCR, multiple primer extension (MPEX), and isothermalsmart amplification. In one embodiment, at least one polymorphism isdetected by amplification of a target region containing at least onepolymorphism, and hybridization with at least one sequence-specificoligonucleotide that hybridizes under stringent conditions to at leastone polymorphism and detecting the hybridization. In one embodiment, thepresence of one or two alleles of the G genotype at the SNP rs4698775,SNP rs17440077, SNP rs1329428, SNP rs429608 or SNP rs2230199 or one ortwo alleles of the A genotype at the SNP rs10737680 in the individualindicates an increased risk for degenerative disease progression. In oneembodiment, a polymorphism that is in linkage disequilibrium with atleast one single nucleotide polymorphism selected from the groupconsisting of single nucleotide polymorphism (SNP) rs4698775,rs17440077, rs10737680, rs1329428, rs429608, and rs2230199 is detected.In one embodiment, the degenerative disease is age related maculardegeneration. In one embodiment, the age related macular degeneration isearly, intermediate or advanced AMD. In one embodiment, the advanced AMDis geographic atrophy.

In one aspect, the invention provides an in vitro use of an agent thatbinds to at least one degenerative disease-associated polymorphismwherein the polymorphism is a risk allele selected from the groupconsisting of a CFI risk allele, a CFH risk allele, a C2 risk allele, aCFB risk allele or a C3 risk allele for identifying a patient having adegenerative disease likely to respond to a therapy comprising ananti-factor D antibody, or antigen binding fragment thereof, wherein thepresence of said polymorphisms identifies that the patient is morelikely to respond to the therapy. In one embodiment, the CFI allele isan equivalent allele thereof, the CFH allele is an equivalent allelethereof, the C2 allele is an equivalent allele thereof, the CFB alleleis an equivalent allele thereof, or the C3 allele is an equivalentallele thereof. In one embodiment, the CFI allele comprises a G at thesingle nucleotide polymorphism (SNP) rs4698775 or rs17440077, the CFHallele comprises an A at the single nucleotide polymorphism (SNP)rs10737680 or a G at the single nucleotide polymorphism (SNP) rs1329428,the C2 allele comprises a G at the single nucleotide polymorphism (SNP)rs429608, the CFB allele comprises a G at the single nucleotidepolymorphism (SNP) rs429608, and the C3 allele comprises a G at thesingle nucleotide polymorphism (SNP) rs2230199. In one embodiment, atleast one polymorphism is detected by a technique selected from thegroup consisting of scanning probe and nanopore DNA sequencing,pyrosequencing, Denaturing Gradient Gel Electrophoresis (DGGE), TemporalTemperature Gradient Electrophoresis (TTGE), Zn(II)-cyclenpolyacrylamide gel electrophoresis, homogeneous fluorescent PCR-basedsingle nucleotide polymorphism analysis, phosphate-affinitypolyacrylamide gel electrophoresis, high-throughput SNP genotypingplatforms, molecular beacons, 5′ nuclease reaction, Taqman assay,MassArray (single base primer extension coupled with matrix-assistedlaser desorption/ionization time-of-flight mass spectrometry), tritylmass tags, genotyping platforms (such as the Invader Assay®), singlebase primer extension (SBE) assays, PCR amplification (e.g. PCRamplification on magnetic nanoparticles (MNPs), restriction enzymeanalysis of PCR products (RFLP methods), allele-specific PCR, multipleprimer extension (MPEX), and isothermal smart amplification. In oneembodiment, at least one polymorphism is detected by amplification of atarget region containing at least one polymorphism, and hybridizationwith at least one sequence-specific oligonucleotide that hybridizesunder stringent conditions to at least one polymorphism and detectingthe hybridization. In one embodiment, the presence of one or two allelesof the G genotype at the SNP rs4698775, SNP rs17440077, SNP rs1329428,SNP rs429608 or SNP rs2230199 or one or two alleles of the A genotype atthe SNP rs10737680 in the individual indicates an increased risk fordegenerative disease progression. In one embodiment, a polymorphism thatis in linkage disequilibrium with at least one single nucleotidepolymorphism selected from the group consisting of single nucleotidepolymorphism (SNP) rs4698775, rs17440077, rs10737680, rs1329428,rs429608, and rs2230199 is detected. In one embodiment, the degenerativedisease is an ocular degenerative disease. In one embodiment, the oculardegenerative disease is age related macular degeneration. In oneembodiment, the age related macular degeneration is early, intermediateor advanced AMD. In one embodiment, the advanced AMD is geographicatrophy.

In one aspect, the invention provides an in vitro use of a degenerativedisease-associated polymorphism for selecting a patient having adegenerative disease as likely to respond to a therapy comprising ananti-factor D antibody, or an antigen-binding fragment thereof, whereinthe patient is identified as more likely to respond to the therapy whenthe degenerative disease-associated polymorphism is detected in thesample from the patient. In one embodiment, the degenerative-diseaseassociated polymorphism is an AMD-associated polymorphism. In oneembodiment, the AMD-associated polymorphism is a risk allele selectedfrom the group consisting of a CFI risk allele, a CFH risk allele, a C2risk allele, a CFB risk allele or a C3 risk allele for identifying apatient having a degenerative disease likely to respond to a therapycomprising an anti-factor D antibody, or antigen binding fragmentthereof, wherein the presence of said polymorphisms identifies that thepatient is more likely to respond to the therapy. In one embodiment, theCFI allele is an equivalent allele thereof, the CFH allele is anequivalent allele thereof, the C2 allele is an equivalent allelethereof, the CFB allele is an equivalent allele thereof, or the C3allele is an equivalent allele thereof. In one embodiment, the CFIallele comprises a G at the single nucleotide polymorphism (SNP)rs4698775 or rs17440077, the CFH allele comprises an A at the singlenucleotide polymorphism (SNP) rs10737680 or a G at the single nucleotidepolymorphism (SNP) rs1329428, the C2 allele comprises a G at the singlenucleotide polymorphism (SNP) rs429608, the CFB allele comprises a G atthe single nucleotide polymorphism (SNP) rs429608, and the C3 allelecomprises a G at the single nucleotide polymorphism (SNP) rs2230199. Inone embodiment, at least one polymorphism is detected by a techniqueselected from the group consisting of scanning probe and nanopore DNAsequencing, pyrosequencing, Denaturing Gradient Gel Electrophoresis(DGGE), Temporal Temperature Gradient Electrophoresis (TTGE),Zn(II)-cyclen polyacrylamide gel electrophoresis, homogeneousfluorescent PCR-based single nucleotide polymorphism analysis,phosphate-affinity polyacrylamide gel electrophoresis, high-throughputSNP genotyping platforms, molecular beacons, 5′ nuclease reaction,Taqman assay, MassArray (single base primer extension coupled withmatrix-assisted laser desorption/ionization time-of-flight massspectrometry), trityl mass tags, genotyping platforms (such as theInvader Assay®), single base primer extension (SBE) assays, PCRamplification (e.g. PCR amplification on magnetic nanoparticles (MNPs),restriction enzyme analysis of PCR products (RFLP methods),allele-specific PCR, multiple primer extension (MPEX), and isothermalsmart amplification. In one embodiment, at least one polymorphism isdetected by amplification of a target region containing at least onepolymorphism, and hybridization with at least one sequence-specificoligonucleotide that hybridizes under stringent conditions to at leastone polymorphism and detecting the hybridization. In one embodiment, thepresence of one or two alleles of the G genotype at the SNP rs4698775,SNP rs17440077, SNP rs1329428, SNP rs429608 or SNP rs2230199 or one ortwo alleles of the A genotype at the SNP rs10737680 in the individualindicates an increased risk for degenerative disease progression. In oneembodiment, a polymorphism that is in linkage disequilibrium with atleast one single nucleotide polymorphism selected from the groupconsisting of single nucleotide polymorphism (SNP) rs4698775,rs17440077, rs10737680, rs1329428, rs429608, and rs2230199 is detected.In one embodiment, the degenerative disease is an ocular degenerativedisease. In one embodiment, the ocular degenerative disease is agerelated macular degeneration. In one embodiment, the age related maculardegeneration is early, intermediate or advanced AMD. In one embodiment,the advanced AMD is geographic atrophy.

In one aspect, the invention provides a use of a degenerativedisease-associated polymorphism for the manufacture of a diagnostic forassessing the likelihood of a response of a patient having adegenerative disease to a therapy comprising an anti-factor D antibody,or an antigen-binding fragment thereof. In one embodiment, thedegenerative-disease associated polymorphism is an AMD-associatedpolymorphism. In one embodiment, the AMD-associated polymorphism is arisk allele selected from the group consisting of a CFI risk allele, aCFH risk allele, a C2 risk allele, a CFB risk allele or a C3 risk allelefor identifying a patient having a degenerative disease likely torespond to a therapy comprising an anti-factor D antibody, or antigenbinding fragment thereof, wherein the presence of said polymorphismsidentifies that the patient is more likely to respond to the therapy. Inone embodiment, the CFI allele is an equivalent allele thereof, the CFHallele is an equivalent allele thereof, the C2 allele is an equivalentallele thereof, the CFB allele is an equivalent allele thereof, or theC3 allele is an equivalent allele thereof. In one embodiment, the CFIallele comprises a G at the single nucleotide polymorphism (SNP)rs4698775 or rs17440077, the CFH allele comprises an A at the singlenucleotide polymorphism (SNP) rs10737680 or a G at the single nucleotidepolymorphism (SNP) rs1329428, the C2 allele comprises a G at the singlenucleotide polymorphism (SNP) rs429608, the CFB allele comprises a G atthe single nucleotide polymorphism (SNP) rs429608, and the C3 allelecomprises a G at the single nucleotide polymorphism (SNP) rs2230199. Inone embodiment, at least one polymorphism is detected by a techniqueselected from the group consisting of scanning probe and nanopore DNAsequencing, pyrosequencing, Denaturing Gradient Gel Electrophoresis(DGGE), Temporal Temperature Gradient Electrophoresis (TTGE),Zn(II)-cyclen polyacrylamide gel electrophoresis, homogeneousfluorescent PCR-based single nucleotide polymorphism analysis,phosphate-affinity polyacrylamide gel electrophoresis, high-throughputSNP genotyping platforms, molecular beacons, 5′ nuclease reaction,Taqman assay, MassArray (single base primer extension coupled withmatrix-assisted laser desorption/ionization time-of-flight massspectrometry), trityl mass tags, genotyping platforms (such as theInvader Assay®), single base primer extension (SBE) assays, PCRamplification (e.g. PCR amplification on magnetic nanoparticles (MNPs),restriction enzyme analysis of PCR products (RFLP methods),allele-specific PCR, multiple primer extension (MPEX), and isothermalsmart amplification. In one embodiment, at least one polymorphism isdetected by amplification of a target region containing at least onepolymorphism, and hybridization with at least one sequence-specificoligonucleotide that hybridizes under stringent conditions to at leastone polymorphism and detecting the hybridization. In one embodiment, thepresence of one or two alleles of the G genotype at the SNP rs4698775,SNP rs17440077, SNP rs1329428, SNP rs429608 or SNP rs2230199 or one ortwo alleles of the A genotype at the SNP rs10737680 in the individualindicates an increased risk for degenerative disease progression. In oneembodiment, a polymorphism that is in linkage disequilibrium with atleast one single nucleotide polymorphism selected from the groupconsisting of single nucleotide polymorphism (SNP) rs4698775,rs17440077, rs10737680, rs1329428, rs429608, and rs2230199 is detected.In one embodiment, the degenerative disease is an ocular degenerativedisease. In one embodiment, the ocular degenerative disease is agerelated macular degeneration. In one embodiment, the age related maculardegeneration is early, intermediate or advanced AMD. In one embodiment,the advanced AMD is geographic atrophy.

In one aspect, the invention provides an oligonucleotide for detectingpolymorphisms at one or more nucleotide positions incomplement-associated loci. In one embodiment, the complement-associatedloci are selected from CFH, CFI, C3, C2 and CFB risk loci. In oneembodiment, the nucleotide position is selected from the groupconsisting of nucleotide positions associated with rs4698775,rs17440077, rs10737680, rs1329428, rs429608 and rs2230199. In oneembodiment the oligonucleotide is at least 90% identical to and havingthe 3′ terminal nucleotide of one or more of the sequences selected fromthe group consisting of SEQ ID NOs:17-41. The oligonucleotides mightcomprise 3 or fewer mismatches with one of said sequences, excluding the3′-terminal nucleotide and/or at least one mismatch among thepenultimate 5 nucleotides at the 3′-terminus. The oligonucleotides mightfurther comprise at least one modified nucleotide among the terminal 5nucleotides at the 3′-terminus. In some embodiments, the oligonucleotideis suitable for detecting one or more of the alleles of rs4698775,rs17440077, rs10737680, rs1329428, rs429608, and rs2230199.

In one aspect, the invention is a diagnostic method of detecting SNPs inthe CFH, CFI, C3, C2 or CFB risk loci. In one embodiment, the SNP isselected from rs4698775, rs17440077, rs10737680, rs1329428, rs429608,and rs2230199. In one embodiment, the SNP is detected usingoligonucleotides selected from SEQ ID NOs:17-41 or variations at least90% identical thereto and having the 3′-terminal nucleotide of saidoligonucleotide. In one embodiment, the method comprises contacting abiological sample containing nucleic acids with one or more of theoligonucleotides in the presence of the corresponding downstream primerand detection probe. Advantageously, detection of several SNPs can beperformed in a single reaction. In some embodiments, several closelypositioned polymorphisms can be detected in a single reaction containingtwo or more allele-specific oligonucleotides, e.g. selected fromsequences listed in Table 9 that can be combined in one reaction mixturewith a single downstream primer and optionally a single detection probe.In a further embodiment, the method comprises contacting a test samplecontaining nucleic acids with one or more of the oligonucleotides asSNP-specific probes in the presence of the corresponding forward andreverse primers (i.e. primers capable of hybridizing to the oppositestrands of the target DNA nucleic acids so as to enable exponentialamplification), nucleoside triphosphates and a nucleic acid polymerase,such that the one or more allele-specific primers is efficientlyextended only when a mutation is present in the sample; and detectingthe presence or absence of a mutation by directly or indirectlydetecting the presence or absence of the primer extension.

In a particular embodiment the presence of the primer extension isdetected with a probe. The probe may be labeled with a radioactive, or achromophore (fluorophore) label, e.g. a label incorporating FAM, JA270,CY5 family dyes, or HEX dyes. As one example of detection using afluorescently labeled probe, the mutation may be detected by real-timepolymerase chain reaction (rt-PCR), where hybridization of the proberesults in enzymatic digestion of the probe and detection of theresulting fluorescence (TaqMan™ probe method, Holland et al. (1991)P.N.A.S. USA 88:7276-7280). Alternatively, the presence of the extensionproduct and the amplification product may be detected by gelelectrophoresis followed by staining or by blotting and hybridization asdescribed e.g., in Sambrook, J. and Russell, D. W. (2001) MolecularCloning, 3^(rd) ed. CSHL Press, Chapters 5 and 9.

In some embodiments, the factor D inhibitor as described herein and inthe uses described herein is an anti-factor D antibody. The antibodyspecifically binds Factor D. In some embodiments, the antibody comprisesa light chain comprising HVR-L1 comprising the amino acid sequenceITSTDIDDDMN (SEQ ID NO:1), HVR-L2 comprising the amino acid sequenceGGNTLRP (SEQ ID NO:2), and HVR-L3 comprising the amino acid sequenceLQSDSLPYT (SEQ ID NO: 3); and/or a heavy chain comprising HVR-H1comprising the amino acid sequence GYTFTNYGMN (SEQ ID NO: 4), HVR-H2comprising the amino acid sequence WINTYTGETTYADDFKG (SEQ ID NO:5), andHVR-H3 comprising the amino acid sequence EGGVNN (SEQ ID NO:6). In someembodiments, the antibody comprises a heavy chain variable regionsequence of at least 95% sequence identity to the amino acid sequence ofSEQ ID NO:7; and/or a light chain variable region sequence of at least95% sequence identity to the amino acid sequence of SEQ ID NO:8. In someembodiments, the antibody comprises a heavy chain variable regioncomprising the amino acid sequence of SEQ ID NO:7; and/or a light chainvariable region comprising the amino acid sequence of SEQ ID NO:8. Insome embodiments, the antibody is lampalizumab having CAS registrationnumber 1278466-20-8. In some embodiments, the anti-factor D antibody maybe a monoclonal antibody, antibody fragment, chimeric antibody,humanized antibody, single-chain antibody or antibody that competitivelyinhibits the binding of an anti-factor D antibody to its respectiveantigenic epitope. In one embodiment, the anti-factor D antibodycompetitively inhibits the binding of the anti-factor D antibodycomprising a light chain comprising HVR-L1 comprising the amino acidsequence ITSTDIDDDMN (SEQ ID NO:1), HVR-L2 comprising the amino acidsequence GGNTLRP (SEQ ID NO:2), and HVR-L3 comprising the amino acidsequence LQSDSLPYT (SEQ ID NO: 3); and/or a heavy chain comprisingHVR-H1 comprising the amino acid sequence GYTFTNYGMN (SEQ ID NO: 4),HVR-H2 comprising the amino acid sequence WINTYTGETTYADDFKG (SEQ IDNO:5), and HVR-H3 comprising the amino acid sequence EGGVNN (SEQ IDNO:6) to its respective antigenic epitope. In one embodiment, theanti-factor D antibody competitively inhibits the binding of theantibody comprising a heavy chain variable region sequence of at least95% sequence identity to the amino acid sequence of SEQ ID NO:7; and/ora light chain variable region sequence of at least 95% sequence identityto the amino acid sequence of SEQ ID NO:8 to its respective antigenicepitope. In one embodiment, the anti-factor D antibody competitivelyinhibits the binding of the antibody comprising a heavy chain sequenceof at least 95% sequence identity to the amino acid sequence of SEQ IDNO:15; and/or a light chain sequence of at least 95% sequence identityto the amino acid sequence of SEQ ID NO:16 to its respective antigenicepitope. In one embodiment, the anti-factor D antibody competitivelyinhibits the binding of the antibody comprising a heavy chain variableregion comprising the amino acid sequence of SEQ ID NO:7; and/or a lightchain variable region comprising the amino acid sequence of SEQ ID NO:8to its respective antigenic epitope. In one embodiment, the anti-factorD antibody competitively inhibits the binding of the antibody comprisinga heavy chain comprising the amino acid sequence of SEQ ID NO:15; and/ora light chain comprising the amino acid sequence of SEQ ID NO:16 to itsrespective antigenic epitope. In one embodiment, the anti-factor Dantibody competitively inhibits the binding of lampalizumab having CASregistration number 1278466-20-8 to its respective antigenic epitope. Insome embodiments, the anti-factor D antibody binds to the same epitopeon factor D bound by another factor D antibody. In one embodiment, theanti-factor D antibody binds to the same epitope on factor D bound bythe anti-factor D antibody comprising a light chain comprising HVR-L1comprising the amino acid sequence ITSTDIDDDMN (SEQ ID NO:1), HVR-L2comprising the amino acid sequence GGNTLRP (SEQ ID NO:2), and HVR-L3comprising the amino acid sequence LQSDSLPYT (SEQ ID NO: 3); and/or aheavy chain comprising HVR-H1 comprising the amino acid sequenceGYTFTNYGMN (SEQ ID NO: 4), HVR-H2 comprising the amino acid sequenceWINTYTGETTYADDFKG (SEQ ID NO:5), and HVR-H3 comprising the amino acidsequence EGGVNN (SEQ ID NO:6). In one embodiment, the anti-factor Dantibody binds to the same epitope on factor D bound by the antibodycomprising a heavy chain variable region sequence of at least 95%sequence identity to the amino acid sequence of SEQ ID NO:7; and/or alight chain variable region sequence of at least 95% sequence identityto the amino acid sequence of SEQ ID NO:8. In one embodiment, theanti-factor D antibody binds to the same epitope on factor D bound bythe antibody comprising a heavy chain sequence of at least 95% sequenceidentity to the amino acid sequence of SEQ ID NO:15; and/or a lightchain sequence of at least 95% sequence identity to the amino acidsequence of SEQ ID NO:16. In one embodiment, the anti-factor D antibodybinds to the same epitope on factor D bound by the antibody comprising aheavy chain variable region comprising the amino acid sequence of SEQ IDNO:7; and/or a light chain variable region comprising the amino acidsequence of SEQ ID NO:8. In one embodiment, the anti-factor D antibodybinds to the same epitope on factor D bound by the antibody comprising aheavy chain comprising the amino acid sequence of SEQ ID NO:15; and/or alight chain comprising the amino acid sequence of SEQ ID NO:16. In oneembodiment, the anti-factor D antibody binds to the same epitope onfactor D bound by lampalizumab having CAS registration number1278466-20-8.

In another aspect, the invention provides an article of manufacturecomprising an IVT administration device, which delivers to a patient aflat dose of an anti-factor D antibody, or antigen-binding fragmentthereof, wherein the flat dose is in the microgram to milligram range.In some embodiments, the flat dose is 10 mg monthly or 10 mg every othermonth. In some embodiments, the concentration of the antibody in thedevice is about 10 mg. In another aspect, the invention provides anarticle of manufacture comprising an anti-factor D antibody, orantigen-binding fragment thereof in a concentration of 10 mg. In someembodiments, the antibody comprises a light chain comprising HVR-L1comprising the amino acid sequence ITSTDIDDDMN (SEQ ID NO:1), HVR-L2comprising the amino acid sequence GGNTLRP (SEQ ID NO:2), and HVR-L3comprising the amino acid sequence LQSDSLPYT (SEQ ID NO: 3); and/or aheavy chain comprising HVR-H1 comprising the amino acid sequenceGYTFTNYGMN (SEQ ID NO: 4), HVR-H2 comprising the amino acid sequenceWINTYTGETTYADDFKG (SEQ ID NO:5), and HVR-H3 comprising the amino acidsequence EGGVNN (SEQ ID NO:6). In some embodiments, the antibodycomprises a heavy chain variable region sequence of at least 95%sequence identity to the amino acid sequence of SEQ ID NO:7; and/or alight chain variable region sequence of at least 95% sequence identityto the amino acid sequence of SEQ ID NO:8. In some embodiments, theantibody comprises a heavy chain variable region comprising the aminoacid sequence of SEQ ID NO:7; and/or a light chain variable regioncomprising the amino acid sequence of SEQ ID NO:8. In some embodiments,the antibody is lampalizumab having CAS registration number1278466-20-8.

In another aspect, the invention provides a kit for identifying adegenerative disease patient who may benefit for a factor D inhibitortreatment, comprising a vial for collecting a blood sample from adegenerative disease patient and instructions for determining whetherthe degenerative disease patient carries a risk allele. In someembodiments, the presence of at least one SNP from the group consistingof complement factor I (CFI), complement factor H(CFH), complementfactor B (CFB), complement component 3 (C3) and complement component 2(C2) is used to determine whether the degenerative disease patientcarries the risk allele. In one embodiment, the degenerative disease isan ocular degenerative disease. In some embodiments, the oculardegenerative disease is AMD. In some embodiments, the factor D inhibitoris an anti-factor D antibody, or antigen-binding fragment thereof.

In another aspect, the invention provides a stable lyophilizedcomposition, which, after reconstitution with sterile water forinjection, comprises an anti-factor D antibody, or antigen-bindingfragment thereof in an amount of about 80 to about 120 mg/mL, sodiumchloride in an amount of about 8 to about 40 mM, sucrose in the amountof about 80 mM to about 240 mM, L-histidine in an amount of about 10 toabout 60 mM, polysorbate 20 in an amount of about 0.01 to about 0.08%w/v, wherein the composition has a pH from about 5.0 to about 6.0.

It is to be understood that one, some, or all of the properties of thevarious embodiments described herein may be combined to form otherembodiments of the present invention. These and other aspects of theinvention will become apparent to one of skill in the art. These andother embodiments of the invention are further described in the detaileddescription that follows.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a diagram of the study design for the MAHALO trialdescribed in Example 1 below.

FIG. 2A is a table summarizing baseline characteristics for allefficacy-evaluable patients (n=123) from the phase II component of thestudy described in Example 1. “Efficacy-evaluable patients” as usedherein are defined as all randomized patients who receive at least oneinjection of treatment and had at least one post-baseline GA areameasurement. FIG. 2B is a table summarizing baseline characteristics ofassayed patients based on CFI status, with risk allele carriers definedas individuals heterozygous or risk-allele homozygous at the SNP beingtested. VA=visual acuity. GA=geographic atrophy. DA=disc area (1 DA=2.54mm²).

FIGS. 3A and 3B show the preliminary efficacy results after the primarydatabase lock for the MAHALO phase II study with an all-cornerspopulation; the study met its primary endpoint of mean change frombaseline in GA area at 18 months as measured by fundus autofluorescence(FAF) and met its secondary endpoint of mean change from baseline in GAarea at 18 months as assessed by color fundus photography (CFP) in thelampalizumab monthly group. A positive treatment effect in slowing theprogression of GA area growth was observed in the monthly groupbeginning at 6 months and extending through 18 months with primary (FAF)and secondary (CFP) imaging endpoints. FIG. 3A shows that on the basisof the unadjusted means with the LOCF data, the lampalizumab monthly armhad a 23.1% reduction in the progression of GA area growth relative tothe pooled sham arm. FIG. 3B shows that on the basis of the leastsquares means from the stratified analysis of variance (Henry Scheffe.Chapter 1.2 “Mathematical Models” in The Analysis of Variance, New York:John Wiley & Sons, Inc., 1999, p. 4-7), stratified by lesion sizecategories at baseline, <4 DA vs.>4 DA) with the LOCF data, thelampalizumab monthly arm had a 20.4% reduction in the progression of GAarea growth relative to the pooled sham arm. The results demonstrated aclinically meaningful and statistically significant effect oflampalizumab administered monthly on reducing GA area growth over the18-month study-treatment period. “Sham pooled” refers to the treatmentgroup receiving sham monthly or sham every other month. “afDlm” refersto the treatment group receiving lampalizumab every month. “afD2 m”refers to the treatment group receiving lampalizumab every other month.LOCF method refers to the last-observation-carried-forward method usedfor the imputation of the missing data (David Streiner.“Last-Observation-Carried-Forward Method” in Encyclopedia of ResearchDesign, Volume 2, Neil Salkind, Ed. Thousand Oaks, Calif.: SagePublications, Inc., 2010, p. 681-745).

FIG. 4 compares the definitive decreased autofluorescence (DDAF) change(DDAF change in GA area as used herein refers to the change in lesionsize (in mm2) from baseline to 18 months) in the sham and lampalizumabmonthly treatment groups. The total number of patients in the sham andlampalizumab monthly treatment group are indicated as “All”. The numberof patients carrying the CFH risk allele (rs1329428), C2/CFB risk allele(rs429608), C3 risk allele (rs2230199) or CFI risk allele (rs17440077)in the sham and lampalizumab monthly treatment groups is indicated. Allpatients carried the C2/CFB risk allele (except 1 patient in the shamgroup). All patients also carried the CFH risk allele (excluding 2patients in the sham group).

FIG. 5 shows the DDAF change (mean sham minus mean monthly treated) and% reduction in GA area (mean sham minus mean monthly treated divided bythe mean ham) in groups at month 18. The total number of patients in thesham and lampalizumab monthly treatment groups are indicated as “All”.The numbers of patients in the sham and lampalizumab monthly treatmentgroups that are heterozygous or homozygous for the CFH risk allele, C2risk allele, CFB risk allele, C3 risk allele or CFI risk allele areindicated. Patients that are heterozygous for the CFI risk allele (thesepatients also carry the C2/CFB and CFH risk alleles) showed a meanchange in GA area in sham versus monthly treated of −2.29 mm² and a %reduction in monthly treated versus sham of 52.66%, indicating lesionprogression rate in the monthly treatment group was significantlyreduced versus the sham control. “DDAF” when used herein refers to GAarea. “DDAF change” when used herein refers to change from baseline.

FIG. 6 shows the least squares mean of DDAF change from baseline in GAarea by FAF in patients carrying the CFH, C2/CFB and CFI risk alleles inthe sham and lampalizumab monthly treatment groups. The data in thisfigure are adjusted for lesion size at baseline as continuous variableand lesion size category at baseline (<4 DA and ≥4 DA). The treatmenteffect and reduction rate are calculated at month 18, the primaryefficacy time point; the absolute treatment effect at month 18 was 1.837mm2 which corresponds to a reduction rate of 44%. Vertical bars are 95%confidence intervals of the least squares mean. Asterisks (*) refer tounadjusted p-value <0.005 based on the mixed effect model with observeddata.

FIG. 7 shows the least squares mean of DDAF change from baseline in GAarea by FAF in patients carrying the CFH, C2/CFB and CFI risk allelescompared to patients carrying the CFH and C2/CFB risk alleles withoutthe CFI risk allele in the sham and lampalizumab monthly treatmentgroups. The data in this figure are adjusted for lesion size at baselineas continuous variable and lesion size category at baseline (<4 DA and≥4 DA). The treatment effect and reduction rate are calculated at month18, the primary efficacy time point. The absolute treatment effect atmonth 18 was 1.837 mm2 which corresponds to a reduction rate of 44% asshown in FIG. 6; however, no treatment effect was observed inlampalizumab treated patients without the CFI risk allele. In addition,patients with the CFI risk allele showed more rapid progression in thesham control group versus the sham group without the CFI risk allele.These findings suggest the CFI biomarker is both prognostic forprogression of AMD (e.g. GA) and predictive for treatment response tolampalizumab. Vertical bars are 95% confidence intervals of the leastsquares mean. Asterisks (*) refer to unadjusted p-value <0.005 based onthe mixed effect model with observed data.

FIG. 8 shows the least squares mean of DDAF change from baseline in GAarea by FAF in patients carrying the CFH, C2/CFB and CFI risk allelesand a baseline BCVA of 20/50-20/100 in the sham and lampalizumab monthlytreatment groups. The data in this figure are adjusted for lesion sizeat baseline as continuous variable and lesion size category at baseline(<4 DA and ≥4 DA). The treatment effect and reduction rate arecalculated at month 18, the primary efficacy time point; the absolutetreatment effect at month 18 was 2.827 mm2 which corresponds to areduction rate of 54%. Vertical bars are 95% confidence intervals of theleast squares mean. Asterisks (*) refer to unadjusted p-value <0.005based on the mixed effect model with observed data.

FIG. 9 shows that mRNA levels of CFI (CFI nRPKM) from the publiclyavailable Cancer Genome Atlas (TCGA) database are highest in livertissue. (RPKM=reads per Kb of transcript length per million mapped read;nRPKM is a normalized value for RPKM accounting for the fact that someareas of the genome sequence more efficiently than others).

FIG. 10 shows the levels of CFI mRNA in normal liver tissue by rs4698775SNP genotype. The rs698775 SNP genotype is significantly associated withCFI mRNA levels in normal TCGA liver samples (p=0.02). Risk allelehomozygotes (GG) have less CFI mRNA than heteorzygotes (GT) who in turnhave less CFI mRNA than non-risk allele homozygotes (TT).

FIG. 11 shows an enrichment of CFI rare missense variation in samplesfrom the MAHALO clinical trial samples compared to controls (p=0.015).

FIG. 12 shows CFI− (CFI− based on rs17440077) rare missense variantcarriers have progression rates (mean change from baseline in GA area)similar to CFI+ (CFI+ based on rs17440077).

DETAILED DESCRIPTION

Unless defined otherwise, technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Singleton et al., Dictionary ofMicrobiology and Molecular Biology 2nd ed., J. Wiley & Sons (New York,N.Y. 1994), and March, Advanced Organic Chemistry Reactions, Mechanismsand Structure 4th ed., John Wiley & Sons (New York, N.Y. 1992), provideone skilled in the art with a general guide to many of the terms used inthe present application.

I. Introduction

The present invention provides, inter alia, methods of treating AMD(e.g. GA, wet (neovascular/exudative), early AMD or intermediate AMD)patients with an anti-factor D antibody, or antigen-binding fragmentthereof, and methods of identifying patients likely to benefit from suchtreatment (e.g. patient stratification), and methods of diagnosingpatients at risk for AMD progression.

II. Definitions

For purposes of interpreting this specification, the followingdefinitions will apply and whenever appropriate, terms used in thesingular will also include the plural and vice versa. In the event thatany definition set forth below conflicts with any document incorporatedherein by reference, the definition set forth below shall control.

As used in this specification and the appended claims, the singularforms “a,” “an” and “the” include plural references unless the contextclearly dictates otherwise. Thus, for example, reference to “a protein”or an “antibody” includes a plurality of proteins or antibodies,respectively; reference to “a cell” includes mixtures of cells, and thelike.

The term “complement-associated disorder” is used in the broadest senseand includes disorders associated with excessive or uncontrolledcomplement activation. They include complement activation duringcardiopulmonary bypass operations; complement activation due toischemia-reperfusion following acute myocardial infarction, aneurysm,stroke, hemorrhagic shock, crush injury, multiple organ failure,hypobolemic shock, intestinal ischemia or other events causing ischemia.Complement activation has also been shown to be associated withinflammatory conditions such as severe burns, endotoxemia, septic shock,adult respiratory distress syndrome, hemodialysis; anaphylactic shock,severe asthma, angioedema, Crohn's disease, sickle cell anemia,poststreptococcal glomerulonephritis and pancreatitis. The disorder maybe the result of an adverse drug reaction, drug allergy, IL-2 inducedvascular leakage syndrome or radiographic contrast media allergy. Italso includes autoimmune disease such as systemic lupus erythematosus,myasthenia gravis, rheumatoid arthritis, Alzheimer's disease andmultiple sclerosis. Complement activation is also associated withtransplant rejection. Complement activation is also associated withocular diseases such as age-related macular degeneration, diabeticretinopathy and other ischemia-related retinopathies, choroidalneovascularization (CNV), geographic atrophy (GA), uveitis, diabeticmacular edema, pathological myopia, von Hippel-Lindau disease,histoplasmosis of the eye, Central Retinal Vein Occlusion (CRVO),corneal neovascularization, and retinal neovascularization.

The term “complement-associated eye condition” is used in the broadestsense and includes all eye conditions the pathology of which involvescomplement, including the classical and the alternative pathways, and inparticular the alternative pathway of complement. Complement-associatedeye conditions include, without limitation, macular degenerativediseases, such as all stages of age-related macular degeneration (AMD),including dry and wet (non-exudative and exudative) forms, choroidalneovascularization (CNV), geographic atrophy (GA), uveitis, diabetic andother ischemia-related retinopathies, and other intraocular neovasculardiseases, such as diabetic macular edema, pathological myopia, vonHippel-Lindau disease, histoplasmosis of the eye, Central Retinal VeinOcclusion (CRVO), corneal neovascularization, and retinalneovascularization. In one example, complement-associated eye conditionsincludes age-related macular degeneration (AMD), including non-exudative(dry or atrophic) and exudative (wet) AMD, choroidal neovascularization(CNV), diabetic retinopathy (DR), geographic atrophy (GA) andendophthalmitis.

“Age-related Macular Degeneration”, also referred to herein as “AMD”, asused herein is a disease of the eye caused by degeneration of the cellsof the macula which is the part of the retina that is responsible forcentral vision. AMD can be either (1) wet (exudative) which ischaracterized by the abnormal growth of blood vessels underneath theretina which leads to leaking of fluid or blood which ultimately damagesthe photoreceptors or (2) dry (non-exudative) which is characterized bythe accumulation of cellular debris called drusen between the retina andthe choroid.

“Geographic Atrophy”, also referred to herein as “GA”, as used herein isa disease involving degeneration of the retinal pigment epithelium(RPE), associated with loss of photoreceptors. GA is the advanced formof dry AMD.

“GA Area”, as used herein refers to a discrete area representing loss ofretinal anatomy (e.g. photoreceptors and retinal pigment epithelium(RPE). GA area is measured by standard imaging techniques such as fundusautofluorescence (FAF) and digital color fundus photography (CFP),

“Early AMD”, as used herein is a disease characterized by multiple small(<63 μm) or ≥1 intermediate drusen (≥63 μm and <125 μm).

“Intermediate AMD”, as used herein is a disease characterized by manyintermediate or ≥1 large drusen (≥125 μm) often accompanied by hyper orhypopigmentation of the retinal pigment epithelium.

“Advanced AMD”, as used herein is a disease characterized by geographicatrophy (GA) or neovascular (wet) AMD).

“Prognostic biomarker”, as used herein is a marker that indicates thelikely course of the disease in an untreated individual.

“Predictive biomarker”, as used herein identifies a subpopulation ofpatients who are most likely to respond to a given treatment.

“Affinity” refers to the strength of the sum total of noncovalentinteractions between a single binding site of a molecule (e.g., anantibody) and its binding partner (e.g., an antigen). Unless indicatedotherwise, as used herein, “binding affinity” refers to intrinsicbinding affinity which reflects a 1:1 interaction between members of abinding pair (e.g., antibody and antigen binding arm). The affinity of amolecule X for its partner Y can generally be represented by thedissociation constant (Kd). Affinity can be measured by common methodsknown in the art, including those described herein. Specificillustrative and exemplary embodiments for measuring binding affinityare described in the following.

An “affinity matured” antibody refers to an antibody with one or morealterations in one or more hypervariable regions (HVRs), compared to aparent antibody which does not possess such alterations, suchalterations resulting in an improvement in the affinity of the antibodyfor antigen.

The terms “anti-target antibody” and “an antibody that binds to target”refer to an antibody that is capable of binding the target (e.g. factorD) with sufficient affinity such that the antibody is useful as adiagonostic and/or therapeutic agent in targeting the target (e.g.factor D). In one embodiment, the extent of binding of an anti-targetantibody to an unrelated, non-target protein is less than about 10% ofthe binding of the antibody to target as measured, e.g., by aradioimmunoassay (RIA) or biacore assay. In certain embodiments, anantibody that binds to a target has a dissociation constant (Kd) of ≤1μM, ≤100 nM, ≤10 nM, ≤1 nM, ≤0.1 nM, ≤0.01 nM, or ≤0.001 nM (e.g. 10-8 Mor less, e.g. from 10-8 M to 10-13 M, e.g., from 10-9 M to 10-13 M). Incertain embodiments, an anti-target antibody binds to an epitope of atarget that is conserved among different species.

The term “antibody” herein is used in the broadest sense andspecifically covers monoclonal antibodies, polyclonal antibodies,multispecific antibodies (e.g. bispecific antibodies) formed from atleast two intact antibodies, and antibody fragments so long as theyexhibit the desired biological activity.

“Antibody fragments” comprise a portion of an intact antibody,preferably comprising the antigen-binding region thereof. Examples ofantibody fragments include Fab, Fab′, F(ab′)₂, and Fv fragments;diabodies; linear antibodies; single-chain antibody molecules; andmultispecific antibodies formed from antibody fragments.

An “antibody that binds to the same epitope” as a reference antibodyrefers to an antibody that blocks binding of the reference antibody toits antigen in a competition assay by 50% or more, and conversely, thereference antibody blocks binding of the antibody to its antigen in acompetition assay by 50% or more. In one aspect, an antibody of theinvention is tested for its antigen binding activity, e.g., by knownmethods such as ELISA, Western Blot, etc. In some embodiments,competition assays may be used to identify an antibody that competeswith a reference antibody for binding to factor D. In certainembodiments, such a competing antibody binds to the same epitope (e.g.,a linear or a conformational epitope) that is bound by a referenceanti-factor D antibody specified herein. Detailed exemplary methods formapping an epitope to which an antibody binds are provided in Morris(1996A) “Epitope Mapping Protocols,” in Methods in Molecular Biologyvol. 66 (Humana Press, Totowa, N.J.). In an exemplary competition assay,immobilized factor D is incubated in a solution comprising a firstlabeled antibody that binds to factor D (e.g. lampalizumab) and a secondunlabeled antibody that is being tested for its ability to compete withthe first antibody for binding to factor D. The second antibody may bepresent in a hybridoma supernatant. As a control, immobilized factor Dis incubated in a solution comprising the first labeled antibody (e.g.lampalizumab), but not the second unlabeled antibody. After incubationunder conditions permissive for binding of the first antibody to factorD, excess unbound antibody is removed, and the amount of labelassociated with immobilized factor D is measured. If the amount of labelassociated with immobilized factor D is substantially reduced in thetest sample relative to the control sample, then that indicates that thesecond antibody is competing with the first antibody (e.g. lampalizumab)for binding to factor D. See Harlow and Lane (1988) Antibodies: ALaboratory Manual ch.14 (Cold Spring Harbor Laboratory, Cold SpringHarbor, N.Y.).

An “acceptor human framework” for the purposes herein is a frameworkcomprising the amino acid sequence of a light chain variable domain (VL)framework or a heavy chain variable domain (VH) framework derived from ahuman immunoglobulin framework or a human consensus framework, asdefined below. An acceptor human framework “derived from” a humanimmunoglobulin framework or a human consensus framework may comprise thesame amino acid sequence thereof, or it may contain amino acid sequencechanges. In some embodiments, the number of amino acid changes are 10 orless, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less,3 or less, or 2 or less. In some embodiments, the VL acceptor humanframework is identical in sequence to the VL human immunoglobulinframework sequence or human consensus framework sequence.

For the purposes herein, an “intact antibody” is one comprising heavy-and light-variable domains as well as an Fc region.

As used herein, “anti-human factor D antibody” means an antibody whichspecifically binds to human factor D in such a manner so as to inhibitor substantially reduce complement activation.

As used herein, the term “factor D” is used herein to refer to nativesequence and variant factor D polypeptides.

A “native sequence” factor D, is a polypeptide having the same aminoacid sequence as a factor D polypeptide derived from nature, regardlessof its mode of preparation. Thus, native sequence factor D can beisolated from nature or can be produced by recombinant and/or syntheticmeans. In addition to a mature factor D protein, such as a mature humanfactor D protein (NM_001928), the term “native sequence factor D”,specifically encompasses naturally-occurring precursor forms of factor D(e.g., an inactive preprotein, which is proteolytically cleaved toproduce the active form), naturally-occurring variant forms (e.g.,alternatively spliced forms) and naturally-occurring allelic variants offactor D, as well as structural conformational variants of factor Dmolecules having the same amino acid sequence as a factor D polypeptidederived from nature. Factor D polypeptides of non-human animals,including higher primates and non-human mammals, are specificallyincluded within this definition.

“Factor D variant” means an active factor D polypeptide as defined belowhaving at least about 80% amino acid sequence identity to a nativesequence factor D polypeptide, such as the native sequence human factorD polypeptide (NM_001928). Ordinarily, a factor D variant will have atleast about 80% amino acid sequence identity, or at least about 85%amino acid sequence identity, or at least about 90% amino acid sequenceidentity, or at least about 95% amino acid sequence identity, or atleast about 98% amino acid sequence identity, or at least about 99%amino acid sequence identity with the mature human amino acid sequence(NM_001928).

The term “factor D inhibitor” as used herein refers to a molecule havingthe ability to inhibit a biological function of wild-type or mutatedfactor D. Accordingly, the term “inhibitor” is defined in the context ofthe biological role of factor D. In one embodiment, a factor D inhibitorreferred to herein specifically inhibits the alternative pathway ofcomplement. A factor D inhibitor can be in any form, so long as it iscapable of inhibiting factor D activity; inhibitors include antibodies(e.g., monoclonal antibodies as defined herein below and as described inU.S. Pat. Nos. 8,067,002 and 8,273,352), small organic/inorganicmolecules, antisense oligonucleotides, aptamers, inhibitorypeptides/polypeptides, inhibitory RNAs (e.g., small interfering RNAs),combinations thereof, etc. Active” or “activity” or “biologicalactivity” in the context of a factor D antagonist or inhibitor of thepresent invention is the ability to antagonize (partially or fullyinhibit) a biological activity of factor D. One example of a biologicalactivity of a factor D antagonist is the ability to achieve a measurableimprovement in the state, e.g. pathology, of a factor D-associateddisease or condition, such as, for example, a complement-associated eyecondition. The activity can be determined in in vitro or in vivo tests,including binding assays, alternative pathway hemolysis assays, using arelevant animal model, or human clinical trials.

The term “biomarker” as used herein refers generally to a molecule,including a single nucleotide polymorphism (SNP), protein, carbohydratestructure, or glycolipid, the expression of which in or on a mammaliantissue or cell can be detected by standard methods (or methods disclosedherein) and is predictive, diagnostic and/or prognostic for a mammaliancell's or tissue's sensitivity to treatment regimens based on inhibitionof complement, e.g. alternative pathway of complement. Optionally, a SNPbiomarker is determined when a SNP (a binary entity) stratifies a groupof individuals into responders and non-responders. For example, given aSNP with two nucleotides, a G and an A in which the A is the riskallele, carriers of the A allele (e.g. AA or GA individuals) respond totreatment whereas individuals without an A allele (e.g. GG individuals)do not respond.

The term “single nucleotide polymorphism” also referred to herein as“SNP” as used herein refers to a single base substitution within a DNAsequence that leads to genetic variability. A nucleotide position in agenome at which more than one sequence is possible in a population isreferred to herein as a “polymorphic site” or “polymorphism”. Apolymorphic site may be a nucleotide sequence of two or morenucleotides, an inserted nucleotide or nucleotide sequence, a deletednucleotide or nucleotide sequence, or a microsatellite, for example. Apolymorphic site that is two or more nucleotides in length may be 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more, 20 or more, 30 or more,50 or more, 75 or more, 100 or more, 500 or more, or about 1000nucleotides in length, where all or some of the nucleotide sequencesdiffer within the region. A polymorphic site which is a singlenucleotide in length is referred to herein as a SNP. When there are two,three or four alternative nucleotide sequences at a polymorphic site,each nucleotide sequence is referred to as a “polymorphic variant” or“nucleic acid variant”. Each possible variant in the DNA sequence isreferred to as an “allele”. Where two polymorphic variants exist, thepolymorphic variant represented in a majority of samples from apopulation is referred to as a “prevalent allele” or “major allele” andthe polymorphic variant that is less prevalent in the population isreferred to as an “uncommon allele” or “minor allele”. An individual whocarries two prevalent alleles or two uncommon alleles is “homozygous”with respect to the polymorphism. An individual who carries oneprevalent allele and one uncommon allele is “heterozygous” with respectto the polymorphism. With C/G or A/T SNPs, the alleles are ambiguous anddependent on the strand used to extract the data from the genotypingplatform. With these C/G or A/T SNPs, the C or G nucleotide or the A orT nucleotide, respectively, may be the risk allele and is determined bycorrelation of allele frequencies. The allele that correlates with anincreased risk for a disease or is associated with an odds ratio orrelative risk of >1 is referred to as the “risk allele” or “effectallele”. The “risk allele” or “effect allele” may be the minor allele ormajor allele. For example the risk allele is the minor allele for SNPsrs4698775, rs17440077 and rs2230199 and the risk allele is the majorallele for SNPs rs10737680, rs1329428 and rs429608 in a population ofindividuals with age-related macular degeneration disease (e.g. majorand minor allele status of an allele is determined in a population ofindividuals with the age-related macular degeneration disease). The term“risk locus” is a region of the genome that harbors a risk alleleassociated with a specific disease (e.g. AMD). In some aspects, risklocus (loci) and risk allele(s) are represented by their associationwith particular genes (e.g. genes in the complement pathway) that areimplicated with a specific disease (e.g. AMD). For example, “CFH riskallele” or “CFH allele” as used interchangeably herein refers to a riskallele associated with the CFH risk locus; “CFI risk allele” or “CFIallele” as used interchangeably herein refers to a risk alleleassocaiated with the CFI risk locus, “C3 risk allele” or “C3 allele” asused interchangeably herein refers to a risk allele associated with theC3 risk locus; “C2 risk allele” or “C2 allele” as used interchangeablyherein refers to a risk allele associated with the C2 risk locus; “CFBrisk allele” or “CFB allele” as used interchangeably herein refers to arisk allele associated with the CFB risk locus; and “C2/CFB risk allele”or “C2/CFB allele” as used interchangeably herein refers to a riskallele associated with the C2/CFB risk locus. “Equivalent allele” or“surrogate allele” as used herein refers to an allele that is expectedto behave similarly to a published risk allele and is selected based onallele frequencies and high r² (≥0.6) and/or high D′ (≥0.6) with thepublished risk alleles and/or selected SNP as defined herein. In oneembodiment, the high r² is ≥0.6, 0.7, 0.8, 0.9 or 1.0. In oneembodiment, the high D′ is ≥0.6, 0.7, 0.8, 0.9 or 1.0. SNPs associatedwith age related macular degeneration include SNPs in loci forcomponents of the complement cascade, including but not limited to CFH,CFI, C3, C2, CFB risk loci (Fritsche et al. (Nature Genetics, 45(4):435-441 (2013)). Such SNPs associated with age related maculardegeneration are referred to herein as “AMD-associated polymorphism”.“Degenerative disease-associated polymorphism” refers to a polymorphismor SNP associated with a degenerative disease and includes age relatedmacular degeneration-associated polymorphisms and/or SNPs. “Linkagedisequilibrium or “LD” when used herein refers to alleles at differentloci that are not associated at random, i.e. not associated inproportion to their frequencies. If the alleles are in positive linkagedisequilibrium, then the alleles occur together more often than expectedassuming statistical independence. Conversely, if the alleles are innegative linkage disequilibrium, then the alleles occur together lessoften than expected assuming statistical independence. “Odds ratio” or“OR” when used herein refers to the ratio of the odds of the disease forindividuals with the marker (allele or polymorphism) relative to theodds of the disease in individuals without the marker (allele orpolymorphism). “Haplotype” when used herein refers to a group of alleleson a single chromosome that are closely enough linked to be inheritedusually as a unit. The SNPs rs4698775 and rs17440077 are located in theCFI risk locus, rs10737680 and rs1329428 are located in the CFH risklocus, rs429608 is located in the C2/CFB risk locus and rs2230199 islocated in the C3 risk locus (Genome Reference Consortium GRCh37; UCSCGenome H19 Assembly; February 2009) The SNP rs4698775 is located atposition 110590479 on human chromosome 4 (Genome Reference ConsortiumGRCh37; UCSC Genome HG19 Assembly; February 2009). The G allele changesthe nucleotide sequence from T to G. The SNP rs17440077 is located atposition 110537567 on human chromosome 4 (Genome Reference ConsortiumGRCh37; UCSC Genome HG19 Assembly; February 2009). The G allele changesthe nucleotide sequence from A to G. The SNP rs10737680 is located atposition 196679455 on human chromosome 1 (Genome Reference ConsortiumGRCh37; UCSC Genome HG19 Assembly; February 2009). The A allele changesthe nucleotide sequence form C to A. The SNP rs1329428 is located atposition 196702810 on human chromosome 1 (Genome Reference ConsortiumGRCh37; UCSC Genome HG19 Assembly; February 2009). The G allele changesthe nucleotide sequence from A to G. The SNP rs429608 is located atposition 31930462 on human chromosome 6 (Genome Reference ConsortiumGRCh37; UCSC Genome HG19 Assembly; February 2009). The G allele changesthe nucleotide sequence from A to G. The SNP rs2230199 is located atposition 6718387 on human chromosome 19 (Genome Reference ConsortiumGRCh37; UCSC Genome HG19 Assembly; February 2009). The G allele changesthe nucleotide sequence from C to G and the encoded amino acid fromarginine to glycine. A polymorphic variant may be detected on either orboth strands of a double-stranded nucleic acid. Also, a polymorphicvariant may be located within an intron or exon of a gene or within aportion of a regulatory region such as a promoter, a 5′ untranslatedregion (UTR), a 3′UTR, and in DNA (e.g. genomic DNA (gDNA) andcomplementary DNA (cDNA)), RNA (e.g. mRNA, tRNA, and RRNA), or apolypeptide. Polymorphic variations may or may not result in detectabledifferences in gene expression, polypeptide structure or polypeptidefunction.

The term “selected SNP” when used herein refers to a SNP selected fromthe group consisting of rs4698775, rs17440077, rs10737680, rs1329428,rs429608, rs2230199.

The term “alternate SNP” when used herein refers to a SNP that isexpected to behave similarly to a selected SNP and is selected based onsimilar allele frequencies and has linkage disequilibrium with aselected SNP as measured by a r²≥0.6 and/or D′≥0.6. Alternate SNPsinclude SNPs listed in Tables 4-7 that are in linkage disequilibrium(with a D′ or r² of ≥0.6) with the SNPs described herein including SNPrs1329428, SNP rs2230199, SNP rs17440077 or SNP rs429608. Alternate SNPsinclude SNPs in linkage disequilibrium (with a D′ or r² of ≥0.6) withthe SNPs described herein including SNP rs2230199 or SNP rs4698775.Terms used in Table 4-7 are defined as follows: (i) MAHALO_SNP refers tothe SNP used in the present anti-factor D study described in Examples1-4; (ii) LD_SNP refers to the SNP in LD with the MAHALO_SNP (eitherrsID designation comes from NCBI dbSNP build 137 (Jun. 6, 2012) orinternal nomenclature designation (e.g. X-XXXXX) including chromosomeand base pair position (first number=chromosome number and second numberafter the hyphen=base pair position) from genome build hg18 (UCSC HG18Genome Assembly; March 2006); (iii) CHR refers to the chromosomelocation of LD_SNP (genome build hg19; UCSC HG19 Genome Assembly;February 2009); (iv) BP refers to the DNA base pair location of theLD_SNP (genome build hg19; UCSC HG19 Genome Assembly; February 2009). R2refers to the r-squared value of MAHALO_SNP and LD_SNP; (v) D′ refers tothe D′ value of MAHALO_SNP and LD_SNP; (vi) Ancestry or “ANC” refers tothe ancestry of the population used to determine r2 and D′ values; (vii)source or “SRC” refers to the database listing common variations in thehuman genome (internal data or “GID” refers to a non-public database,1000GP or “GP” refers to the 1000 genomes project public database (1000Genomes Project Consortium et al., Nature, 467(7319): 1061-73 (2010))and Hapmap or “HM” refers to the HapMap public database (InternationalHapMap Consortium, Nature, 437(7063): 1299-320 (2005)). Populationsdescriptions include: Caucasian (CAU); African ancestry in Southwest USA(ASW (A)); Utah residents with Northern and Western European ancestryfrom the CEPH collection (CEU (C)); Han Chinese in Beijing, China (CHB(H)); Chinese in Metropolitan Denver, Colo. (CHD (D)); Gujarati Indiansin Houston, Tex. (GIH (G)); Japanese in Tokyo, Japan (JPT (J)); Luhya inWebuye, Kenya (LWK (L)); Mexican ancestry in Los Angeles, Calif. (MEX(M)); Maasai in Kinyawa, Kenya (MKK (K)); Tuscan in Italy (TSI (T));Yoruban in Ibadan, Nigeria (YR1 (Y)). Table 4 shows LD_SNPs in linkagedisequilibrium (LD) with MAHALO_SNP rs17440077. Table 5 shows LD_SNPs inlinkage disequilibrium (LD) with MAHALO_SNP rs2230199. Table 6 showsLD_SNPs in linkage disequilibrium (LD) with MAHALO_SNP rs429608. Table 7shows LD_SNPs in linkage disequilibrium (LD) with MAHALO_SNP rs1329428.

The present invention provides methods of using the SNPs or othergenetic based mechanisms as a predictive biomarker to predict responseto treatment and as a prognostic biomarker to assess progression of AMD,methods of using the SNPs or other genetic based mechanism to select atreatment strategy, and methods of using the SNPs or other genetic basedmechanisms for patient stratification including but not limited toselecting patients for clinical studies or to make clinical treatmentdecisions. “Patient stratification” when used herein refers togenotyping of individuals to determine the likelihood of response totreatment. The genotyping is performed to identify whether theindividual carries a SNP. Many methods exist for the measurement ofspecific SNP genotypes. Individuals that carry mutations in one or moreSNPs may be detected at the DNA level by a variety of techniquesincluding but not limited to SNP array, Taqman, fluorescencepolarization, Sequenom (or other methods for analysis of SNPs asdescribed herein). Nucleic acids for diagnosis may be obtained from apatient's cells, such as from blood, urine, saliva, tissue biopsy andautopsy material.

“Increased risk” when used herein refers to when the presence in thegenome of an individual of a particular base, at a particular locationin the genome correlates with an increased probability of thatindividual developing more advanced forms of AMD vis-à-vis a populationnot having that base at that location in the genome, that individual issaid to be at “increased risk” of developing more advanced forms of AMD,i.e. to have an increased susceptibility. In the present case, suchincreased probability exists when the base is present in one or theother or both alleles of the individual. Furthermore, the probability isincreased when the base is present in both alleles of the individualrather than one allele of the individual.

“Decreased risk” when used herein refers to when the presence in thegenome of an individual of a particular base, at a particular locationin the genome correlates with an decreased probability of thatindividual developing more advanced forms of AMD vis-à-vis a populationnot having that base at that location in the genome, that individual issaid to be at “decreased risk” of developing more advanced forms of AMD,i.e. to have an decreased susceptibility. Such an allele is sometimesreferred to in the art as being “protective”. As with increased risk, itis also possible for a decreased risk to be characterized as dominant orrecessive.

An “altered risk” means an increased or a decreased risk.

The genomic DNA may be used directly for detection or may be amplifiedby using PCR prior to analysis of the genomic DNA or transcripts. Forexample, fragmented single-stranded DNA from an individual is hybridizedto an array containing hundreds to thousands of immobilized uniquenucleotide probe sequences. The nucleotide probe sequences are designedto bind to a target DNA sequence (e.g. for a SNP, an allele-specificprobe is used to identify and analyze the presence or absence of theSNP). A detection system is used to record and interpret thehybridization signal between the immobilized probe and the DNA from theindividual (either the probe or the DNA is labeled with a fluorophorthat is detected and measured). The detection of a specific DNA sequencemay be achieved by methods which include, but are not limited to,hybridization, RNAse protection, chemical cleavage, direct DNAsequencing or the use of restriction enzymes, Southern blotting ofgenomic DNA, in situ analysis, hybridizing a sample and control nucleicacids to high density arrays containing hundreds or thousands ofoligonucleotide probes (Cronin et al., Hum Mutat, 7(3): 244-55 (1996)(or other methods for analysis of SNPs as described herein). Forexample, genetic mutations can be identified using microarrays (Shen etal., Mutat Res, 573(1-2): 70-82 (2005))). These genetic tests are usefulfor stratifying populations of individuals into subpopulations havingdifferent responsiveness to treatment of anti-factor D.

The term “genotyping” as used herein refers to methods of determiningdifferences in the genetic make-up (“genotype”) of an individual,including but not limited to the detection of the presence of DNAinsertions or deletions, polymorphisms (SNPs or otherwise), alleles(including minor or major or risk alleles in the form of SNPs, byexamining the individual's DNA sequence using analytical or biologicalassays (or other methods for analysis of SNPs as described herein)). Forinstance, the individual's DNA sequence determined by sequencing orother methodologies (for example other methods for analysis of SNPs asdescribed herein), may be compared to another individual's sequence or areference sequence. Methods of genotyping are generally known in the art(for example other methods for analysis of SNPs as described herein),including but are not limited to restriction fragment lengthpolymorphism identification (RFLP) of genomic DNA, random amplifiedpolymorphic detection (RAPD) of genomic DNA, amplified fragment lengthpolymorphism detection (AFLPD), polymerase chain reaction (PCR), DNAsequencing, allele specific oligonucleotide (ASO) probes, andhybridization to DNA microarrays or beads. Similarly these techniquesmay be applied to analysis of transcripts that encode SNPs or othergenetic factors. Samples can be conveniently assayed for a SNP usingpolymerase chain reaction (PCR) analysis, array hybridization or usingDNA SNP chip microarrays, which are commercially available, includingDNA microarray snapshots. A microarray can be utilized for determiningwhether a SNP is present or absent in a nucleic acid sample. Amicroarray may include oligonucleotides, and methods for making andusing oligonucleotide microarrays suitable for diagnostic use aredisclosed in U.S. Pat. Nos. 5,492,806; 5,525,464; 5,589,330; 5,695,940;5,849,483; 6,018,041; 6,045,996; 6,136,541; 6,152,681; 6,156,501;6,197,506; 6,223,127; 6,225,625; 6,229, 911; 6,239,273; WO 00/52625; WO01/25485; and WO 01/29259.

In some embodiments, the genotyping may be used by clinicians to directappropriate treatment procedures to individuals who most require them.For example, subjects in a study are genotyped and categorized into (1)a population that responds favorably to a treatment and (2) a populationthat does not respond significantly to a treatment, and (3) a populationthat responds adversely to a treatment. Based on the results, a subjectis genotyped to predict whether the subject will respond favorably, notrespond significantly or respond adversely to a treatment. Potentialparticipants in clinical trials of a treatment may be screened toidentify those that are most likely to respond favorably to thetreatment and to exclude those likely to experience side effects. Thus,the effectiveness of drug treatment may be measured in individuals whorespond positively to the drug. Thus, one embodiment is a method ofselecting an individual for inclusion in a clinical trial of a treatmentcomprising the steps of: (a) obtaining a nucleic acid sample from anindividual, (b) determining the presence of a polymorphic variant whichis associated with a positive response to the treatment or a polymorphicvariant which is associated with a negative response to the treatment.In another embodiment, the invention includes a method of selecting anindividual for treatment comprising the steps of: (a) obtaining anucleic acid sample from an individual, (b) determining the presence ofa polymorphic variant which is associated with a positive response tothe treatment and (c) treating the individual by administering thetreatment.

The term “allele-specific primer” or “AS primer” refers to a primer thathybridizes to more than one variant of the target sequence, but iscapable of discriminating between the variants of the target sequence inthat only with one of the variants, the primer is efficiently extendedby the nucleic acid polymerase under suitable conditions. With othervariants of the target sequence, the extension is less efficient orinefficient. Where extension is less efficient or inefficient, thesignal is of substantially lesser intensity or preferably, falls belowdetection limit.

The term “allele-specific probe” or “AS probe” refers to a probe thathybridizes to more than one variant of the target sequence, but iscapable of discriminating between the variants of the target sequence inthat only with one of the variants, a detectable signal is generated.With other variants of the target sequence, the signal is ofsubstantially lesser intensity or preferably, falls below the detectionlimit.

The term “primary sequence” refers to the sequence of nucleotides in apolynucleotide or oligonucleotide. Nucleotide modifications such asnitrogenous base modifications, sugar modifications or other backbonemodifications are not a part of the primary sequence. Labels, such aschromophores conjugated to the oligonucleotides are also not a part ofthe primary sequence. Thus two oligonucleotides can share the sameprimary sequence but differ with respect to the modifications andlabels.

The term “primer” refers to an oligonucleotide which hybridizes with asequence in the target nucleic acid and is capable of acting as a pointof initiation of synthesis along a complementary strand of nucleic acidunder conditions suitable for such synthesis. As used herein, the term“probe” refers to an oligonucleotide which hybridizes with a sequence inthe target nucleic acid and is usually detectably labeled. The probe canhave modifications, such as a 3′-terminus modification that makes theprobe non-extendable by nucleic acid polymerases, and one or morechromophores. An oligonucleotide with the same sequence may serve as aprimer in one assay and a probe in a different assay.

he term “modified nucleotide” refers to a unit in a nucleic acid polymerthat contains a modified base, sugar or phosphate group, or thatincorporates a non-natural moiety in its structure. Examples ofnon-natural nucleotides, include nucleotides with a modified nitrogenousbase, e.g. alkylated or otherwise substitutes with a group not presentamong the conventional nitrogenous bases involved in Watson-Crickpairing. By way of illustration and not limitation, modified nucleotidesinclude those with bases substituted with methyl, ethyl, benzyl orbutyl-benzyl. In an allele-specific PCR, at least one primer isallele-specific such that primer extension occurs only (orpreferentially) when the specific variant of the sequence is present anddoes not occur (or occurs less efficiently, i.e. with a substantial ΔCt)when another variant is present. Design of successful allele-specificprimers is an unpredictable art. While it is routine to design a primerfor a known sequence, no formula exists for designing a primer that candiscriminate between very similar sequences. The discrimination isespecially challenging when one or more allele-specific primerstargeting one or more polymorphic sites are present in the same reactionmixture.

The terms “complementary” or “complementarity” are used in reference toantiparallel strands of polynucleotides related by the Watson-Crickbase-pairing rules. The terms “perfectly complementary” or “100%complementary” refer to complementary sequences that have Watson-Crickpairing of all the bases between the antiparallel strands, i.e. thereare no mismatches between any two bases in the polynucleotide duplex.However, duplexes are formed between antiparallel strands even in theabsence of perfect complementarity. The terms “partially complementary”or “incompletely complementary” refer to any alignment of bases betweenantiparallel polynucleotide strands that is less than 100% perfect(e.g., there exists at least one mismatch or unmatched base in thepolynucleotide duplex). The duplexes between partially complementarystrands are generally less stable than the duplexes between perfectlycomplementary strands.

A “phenotype” is a trait which can be compared between individuals, suchas presence or absence of a condition, for example, occurred ofintermediate or advanced AMD.

The nucleic acid sample is isolated from a biological sample obtainedfrom a subject. “Biological sample” includes but is not limited toblood, saliva, sputum, urine, cell scrapings and biopsy tissue. Thenucleic acid sample may be isolated form a biological sample usingstandard techniques. The nucleic acid sample may be used in a method fordetermining the presence of a polymorphic variant. The presence orabsence of a polymorphic variant may be determined using one or bothchromosomal complements represented in the nucleic acid sample.Determining the presence or absence of the polymorphic variant in bothchromosomal complements represented in the nucleic acid sample is usefulfor determining the zygosity of an individual for the polymorphicvariant.

“Stringency” of hybridization reactions is readily determinable by oneof ordinary skill in the art, and generally is an empirical calculationdependent upon probe length, washing temperature, and saltconcentration. In general, longer probes require higher temperatures forproper annealing, while shorter probes need lower temperatures.Hybridization generally depends on the ability of denatured DNA toreanneal when complementary strands are present in an environment belowtheir melting temperature. The higher the degree of desired homologybetween the probe and hybridizable sequence, the higher the relativetemperature which can be used. As a result, it follows that higherrelative temperatures would tend to make the reaction conditions morestringent, while lower temperatures less so. For additional details andexplanation of stringency of hybridization reactions, see Ausubel etal., Current Protocols in Molecular Biology, Wiley IntersciencePublishers, (1995).

“Stringent conditions” or “high stringency conditions”, as definedherein, may be identified by those that: (1) employ low ionic strengthand high temperature for washing, for example 0.015 M sodiumchloride/0.0015 M sodium citrate/0.1% sodium dodecyl sulfate at 50° C.;(2) employ during hybridization a denaturing agent, such as formamide,for example, 50% (v/v) formamide with 0.1% bovine serum albumin/0.1%Ficoll/0.1% polyvinylpyrrolidone/50 mM sodium phosphate buffer at pH 6.5with 750 mM sodium chloride, 75 mM sodium citrate at 42° C.; or (3)overnight hybridization in a solution that employs 50% formamide, 5×SSC(0.75 M NaCl, 0.075 M sodium citrate), 50 mM sodium phosphate (pH 6.8),0.1% sodium pyrophosphate, 5×Denhardt's solution, sonicated salmon spermDNA (50 μg/ml), 0.1% SDS, and 10% dextran sulfate at 42° C., with a 10minute wash at 42° C. in 0.2×SSC (sodium chloride/sodium citrate)followed by a 10 minute high-stringency wash consisting of 0.1×SSCcontaining EDTA at 55° C.

“Moderately stringent conditions” may be identified as described bySambrook et al., Molecular Cloning: A Laboratory Manual, New York: ColdSpring Harbor Press, 1989, and include the use of washing solution andhybridization conditions (e.g., temperature, ionic strength and % SDS)less stringent that those described above. An example of moderatelystringent conditions is overnight incubation at 37° C. in a solutioncomprising: 20% formamide, 5×SSC (150 mM NaCl, 15 mM trisodium citrate),50 mM sodium phosphate (pH 7.6), 5×Denhardt's solution, 10% dextransulfate, and 20 mg/ml denatured sheared salmon sperm DNA, followed bywashing the filters in 1×SSC at about 37-50° C. The skilled artisan willrecognize how to adjust the temperature, ionic strength, etc. asnecessary to accommodate factors such as probe length and the like.

The term “sample,” or “test sample” as used herein, refers to acomposition that is obtained or derived from a subject of interest thatcontains a cellular and/or other molecular entity that is to becharacterized and/or identified, for example based on physical,biochemical, chemical and/or physiological characteristics. In oneembodiment, the definition encompasses blood and other liquid samples ofbiological origin and tissue samples such as a biopsy specimen or tissuecultures or cells derived therefrom. The source of the tissue sample maybe solid tissue as from a fresh, frozen and/or preserved organ or tissuesample or biopsy or aspirate; blood or any blood constituents; bodilyfluids; and cells from any time in gestation or development of thesubject or plasma. The term “sample,” “biological sample,’ or “testsample” includes biological samples that have been manipulated in anyway after their procurement, such as by treatment with reagents,solubilization, or enrichment for certain components, such as proteinsor polynucleotides, or embedding in a semi-solid or solid matrix forsectioning purposes. For the purposes herein a “section” of a tissuesample is meant a single part or piece of a tissue sample, e.g. a thinslice of tissue or cells cut from a tissue sample. Samples include, butare not limited to, whole blood, blood-derived cells, serum, plasma,lymph fluid, synovial fluid, cellular extracts, and combinationsthereof. In one embodiment, the sample is a clinical sample. In anotherembodiment, the sample is used in a diagnostic assay.

In one embodiment, a sample is obtained from a subject or patient priorto treatment with a complement inhibitor. In another embodiment, asample is obtained from a subject or patient following at least onetreatment with a complement inhibitor.

A “reference sample,” as used herein, refers to any sample, standard, orlevel that is used for comparison purposes. In one embodiment, areference sample is obtained from a healthy and/or non-diseased part ofthe body (e.g., tissue or cells) of the same subject or patient. Inanother embodiment, a reference sample is obtained from an untreatedtissue and/or cell of the body of the same subject or patient. In yetanother embodiment, a reference sample is obtained from a healthy and/ornon-diseased part of the body (e.g., tissues or cells) of an individualwho is not the subject or patient. In even another embodiment, areference sample is obtained from an untreated tissue and/or cell partof the body of an individual who is not the subject or patient.

In certain embodiments, a reference sample is a single sample orcombined multiple samples from the same subject or patient that areobtained at one or more different time points than when the test sampleis obtained. For example, a reference sample is obtained at an earliertime point from the same subject or patient than when the test sample isobtained. In certain embodiments, a reference sample includes all typesof biological samples as defined above under the term “sample” that isobtained from one or more individuals who is not the subject or patient.In certain embodiments, a reference sample is obtained from one or moreindividuals with a degenerative disease (e.g., age-related maculardegeneration) who is not the subject or patient.

In certain embodiments, a reference sample is a combined multiplesamples from one or more healthy individuals who are not the subject orpatient. In certain embodiments, a reference sample is a combinedmultiple samples from one or more individuals with a disease or disorder(e.g., an degenerative disease such as, for example, age-related maculardegeneration) who are not the subject or patient. In certainembodiments, a reference sample is pooled RNA samples from normaltissues or pooled plasma or serum samples from one or more individualswho are not the subject or patient.

The terms “Fc receptor” and “FcR” are used to describe a receptor thatbinds to the Fc region of an antibody. The preferred FcR is anative-sequence human FcR. Moreover, a preferred FcR is one that bindsan IgG antibody (a gamma receptor) and includes receptors of the FcγRI,FcγRII, and Fcγ RIII subclasses, including allelic variants andalternatively spliced forms of these receptors. FcγRII receptors includeFcγRIIA (an “activating receptor”) and FcγRIIB (an “inhibitingreceptor”), which have similar amino acid sequences that differprimarily in the cytoplasmic domains thereof. Activating receptorFcγRIIA contains an immunoreceptor tyrosine-based activation motif(ITAM) in its cytoplasmic domain. Inhibiting receptor FcγRIIB containsan immunoreceptor tyrosine-based inhibition motif (ITIM) in itscytoplasmic domain (see Daëron Annu. Rev. Immunol. 15:203-234 (1997)).FcRs are reviewed in Ravetch and Kinet Annu. Rev. Immunol 9:457-92(1991); Capel et al. Immunomethods 4:25-34 (1994); and de Haas et al. J.Lab. Clin. Med. 126:330-41 (1995). Other FcRs, including those to beidentified in the future, are encompassed by the term “FcR” herein. Theterm also includes the neonatal receptor, FcRn, which is responsible forthe transfer of maternal IgGs to the fetus (Guyer et al, J. Immunol.117:587 (1976) and Kim et al. J. Immunol. 24:249 (1994)).

“Native antibodies” are usually heterotetrameric glycoproteins of about150,000 daltons, composed of two identical light (L) chains and twoidentical heavy (H) chains. Each light chain is linked to a heavy chainby one covalent disulfide bond, while the number of disulfide linkagesvaries among the heavy chains of different immunoglobulin isotypes. Eachheavy and light chain also has regularly spaced intrachain disulfidebridges. Each heavy chain has at one end a variable domain (V_(H))followed by a number of constant domains. Each light chain has avariable domain at one end (V_(L)) and a constant domain at its otherend; the constant domain of the light chain is aligned with the firstconstant domain of the heavy chain, and the light-chain variable domainis aligned with the variable domain of the heavy chain. Particular aminoacid residues are believed to form an interface between the light-chainand heavy-chain variable domains.

The term “variable” refers to the fact that certain portions of thevariable domains differ extensively in sequence among antibodies and areused in the binding and specificity of each particular antibody for itsparticular antigen. However, the variability is not evenly distributedthroughout the variable domains of antibodies. It is concentrated inthree segments called hypervariable regions both in the light-chain andthe heavy-chain variable domains. The more highly conserved portions ofvariable domains are called the framework regions (FRs). The variabledomains of native heavy and light chains each comprise four FRs, largelyadopting a β-sheet configuration, connected by three hypervariableregions, which form loops connecting, and in some cases forming part of,the β-sheet structure. The hypervariable regions in each chain are heldtogether in close proximity by the FRs and, with the hypervariableregions from the other chain, contribute to the formation of theantigen-binding site of antibodies (see Kabat et al. Sequences ofProteins of Immunological Interest, 5th Ed. Public Health Service,National Institutes of Health, Bethesda, Md. (1991)). The constantdomains are not involved directly in binding an antibody to an antigen,but exhibit various effector functions, such as participation of theantibody in ADCC.

Papain digestion of antibodies produces two identical antigen-bindingfragments, called “Fab” fragments, each with a single antigen-bindingsite, and a residual “Fc” fragment, whose name reflects its ability tocrystallize readily. Pepsin treatment yields an F(ab′)₂ fragment thathas two antigen-binding sites and is still capable of cross-linkingantigen.

“Fv” is the minimum antibody fragment that contains a completeantigen-recognition and antigen-binding site. This region consists of adimer of one heavy-chain and one light-chain variable domain in tight,non-covalent association. It is in this configuration that the threehypervariable regions of each variable domain interact to define anantigen-binding site on the surface of the V_(H)-V_(L) dimer.Collectively, the six hypervariable regions confer antigen-bindingspecificity to the antibody. However, even a single variable domain (orhalf of an Fv comprising only three hypervariable regions specific foran antigen) has the ability to recognize and bind antigen, although at alower affinity than the entire binding site.

The Fab fragment also contains the constant domain of the light chainand the first constant domain (CH1) of the heavy chain. Fab′ fragmentsdiffer from Fab fragments by the addition of a few residues at thecarboxy terminus of the heavy-chain CH1 domain including one or morecysteines from the antibody hinge region. Fab′-SH is the designationherein for Fab′ in which the cysteine residue(s) of the constant domainsbear at least one free thiol group. F(ab′)₂ antibody fragmentsoriginally were produced as pairs of Fab′ fragments that have hingecysteines between them. Other chemical couplings of antibody fragmentsare also known.

The “light chains” of antibodies (immunoglobulins) from any vertebratespecies can be assigned to one of two clearly distinct types, calledkappa (κ) and lambda (λ), based on the amino acid sequences of theirconstant domains.

Depending on the amino acid sequence of the constant domain of theirheavy chains, antibodies can be assigned to different classes. There arefive major classes of intact antibodies: IgA, IgD, IgE, IgG, and IgM,and several of these may be further divided into subclasses (isotypes),e.g., IgG1, IgG2, IgG3, IgG4, IgA, and IgA2. The heavy-chain constantdomains that correspond to the different classes of antibodies arecalled α, δ, ε, γ, and μ, respectively. The subunit structures andthree-dimensional configurations of different classes of immunoglobulinsare well known.

“Single-chain Fv” or “scFv” antibody fragments comprise the V_(H) andV_(L) domains of antibody, wherein these domains are present in a singlepolypeptide chain. Preferably, the Fv polypeptide further comprises apolypeptide linker between the V_(H) and V_(L) domains that enables thescFv to form the desired structure for antigen binding. For a review ofscFv, see Pliickthun in The Pharmacology of Monoclonal Antibodies, vol.113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315(1994).

The term “diabodies” refers to small antibody fragments with twoantigen-binding sites, which fragments comprise a heavy-chain variabledomain (V_(H)) connected to a light-chain variable domain (V_(L)) in thesame polypeptide chain (V_(H)-V_(L)). By using a linker that is tooshort to allow pairing between the two domains on the same chain, thedomains are forced to pair with the complementary domains of anotherchain and create two antigen-binding sites. Diabodies are described morefully in, for example, EP 404,097; WO 1993/11161; and Hollinger et al.,Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993).

The term “monoclonal antibody” as used herein refers to an antibodyobtained from a population of substantially homogeneous antibodies,i.e., the individual antibodies comprising the population are identicaland/or bind the same epitope, except for possible variants that mayarise during production of the monoclonal antibody, such variantsgenerally being present in minor amounts. In contrast to polyclonalantibody preparations that typically include different antibodiesdirected against different determinants (epitopes), each monoclonalantibody is directed against a single determinant on the antigen. Inaddition to their specificity, the monoclonal antibodies areadvantageous in that they are uncontaminated by other immunoglobulins.The modifier “monoclonal” indicates the character of the antibody asbeing obtained from a substantially homogeneous population ofantibodies, and is not to be construed as requiring production of theantibody by any particular method. For example, the monoclonalantibodies to be used in accordance with the present invention may bemade by the hybridoma method first described by Kohler et al., Nature,256:495 (1975), or may be made by recombinant DNA methods (see, e.g.,U.S. Pat. No. 4,816,567). The “monoclonal antibodies” may also beisolated from phage antibody libraries using the techniques described inClackson et al., Nature, 352:624-628 (1991) and Marks et al., J. Mol.Biol., 222:581-597 (1991), for example.

The monoclonal antibodies herein specifically include “chimeric”antibodies (immunoglobulins) in which a portion of the heavy and/orlight chain is identical with or homologous to corresponding sequencesin antibodies derived from a particular species or belonging to aparticular antibody class or subclass, while the remainder of thechain(s) is identical with or homologous to corresponding sequences inantibodies derived from another species or belonging to another antibodyclass or subclass, as well as fragments of such antibodies, so long asthey exhibit the desired biological activity (U.S. Pat. No. 4,816,567;Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984)).Chimeric antibodies of interest herein include “primatized” antibodiescomprising variable-domain antigen-binding sequences derived from anon-human primate (e.g. Old World Monkey, such as baboon, rhesus, orcynomolgus monkey) and human constant-region sequences (U.S. Pat. No.5,693,780).

“Humanized” forms of non-human (e.g., murine) antibodies are chimericantibodies that contain minimal sequence derived from non-humanimmunoglobulin. For the most part, humanized antibodies are humanimmunoglobulins (recipient antibody) in which residues from ahypervariable region of the recipient are replaced by residues from ahypervariable region of a non-human species (donor antibody) such asmouse, rat, rabbit, or nonhuman primate having the desired specificity,affinity, and capacity. In some instances, framework region (FR)residues of the human immunoglobulin are replaced by correspondingnon-human residues. Furthermore, humanized antibodies may compriseresidues that are not found in the recipient antibody or in the donorantibody. These modifications are made to further refine antibodyperformance. In general, the humanized antibody will comprisesubstantially all of at least one, and typically two, variable domains,in which all or substantially all of the hypervariable loops correspondto those of a non-human immunoglobulin and all or substantially all ofthe FRs are those of a human immunoglobulin sequence, except for FRsubstitution(s) as noted above. The humanized antibody optionally alsowill comprise at least a portion of an immunoglobulin constant region,typically that of a human immunoglobulin. For further details, see Joneset al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-329(1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992).

“Framework” or “FR” refers to variable domain residues other thanhypervariable region (HVR) residues. The FR of a variable domaingenerally consists of four FR domains: FR1, FR2, FR3, and FR4.Accordingly, the HVR and FR sequences generally appear in the followingsequence in VH (or VL): FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

The term “hypervariable region” or “HVR,” as used herein, refers to eachof the regions of an antibody variable domain which are hypervariable insequence and/or form structurally defined loops (“hypervariable loops”).Generally, native four-chain antibodies comprise six HVRs; three in theVH (H1, H2, H3), and three in the VL (L1, L2, L3). HVRs generallycomprise amino acid residues from the hypervariable loops and/or fromthe “complementarity determining regions” (CDRs), the latter being ofhighest sequence variability and/or involved in antigen recognition. AnHVR as used herein comprise any number of residues located withinpositions 24-36 (for L1), 46-56 (for L2), 89-97 (for L3), 26-35B (forH1), 47-65 (for H2), and 93-102 (for H3). Therefore, an HVR includesresidues in positions described previously:

-   -   A) 24-34 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2),        and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901-917        (1987);    -   B) 24-34 of L1, 50-56 of L2, 89-97 of L3, 31-35B of H1, 50-65 of        H2, and 95-102 of H3 (Kabat et al., Sequences of Proteins of        Immunological Interest, 5th Ed. Public Health Service, National        Institutes of Health, Bethesda, Md. (1991).    -   C) 30-36 (L1), 46-55 (L2), 89-96 (L3), 30-35 (H1), 47-58 (H2),        93-100a-j (H3) (MacCallum et al. J. Mol. Biol. 262:732-745        (1996).

Unless otherwise indicated, HVR residues and other residues in thevariable domain (e.g., FR residues) are numbered herein according toKabat et al., supra. The Kabat numbering system is generally used whenreferring to a residue in the variable domain (approximately residues1-107 of the light chain and residues 1-113 of the heavy chain) (e.g,Kabat et al., Sequences of Immunological Interest. 5th Ed. Public HealthService, National Institutes of Health, Bethesda, Md. (1991), expresslyincorporated herein by reference). The “EU numbering system” or “EUindex” is generally used when referring to a residue in animmunoglobulin heavy chain constant region (e.g., the EU index reportedin Kabat et al., supra; hinge region in constant domain of heavy chainis approximately residues 216-230 (EU numbering) of the heavy chain).The “EU index as in Kabat” refers to the residue numbering of the humanIgG1 EU antibody. Unless stated otherwise herein, references to residuenumbers in the variable domain of antibodies means residue numbering bythe Kabat numbering system. Unless stated otherwise herein, referencesto residue numbers in the constant domain of antibodies means residuenumbering by the EU numbering system (e.g., see U.S. ProvisionalApplication No. 60/640,323, Figures for EU numbering).

A “naked antibody” is an antibody (as herein defined) that is notconjugated to a heterologous molecule, such as a cytotoxic moiety orradiolabel.

An “isolated” antibody is one that has been identified and separatedand/or recovered from a component of its natural environment.Contaminant components of its natural environment are materials thatwould interfere with diagnostic or therapeutic uses for the antibody,and may include enzymes, hormones, and other proteinaceous ornon-proteinaceous solutes. In preferred embodiments, the antibody willbe purified (1) to greater than 95% by weight of antibody as determinedby the Lowry method, and most preferably more than 99% by weight, (2) toa degree sufficient to obtain at least 15 residues of N-terminal orinternal amino acid sequence by use of a spinning-cup sequenator, or (3)to homogeneity by SDS-PAGE under reducing or nonreducing conditionsusing Coomassie blue or, preferably, silver stain. Isolated antibodyincludes the antibody in situ within recombinant cells, since at leastone component of the antibody's natural environment will not be present.Ordinarily, however, isolated antibody will be prepared by at least onepurification step.

“Percent (%) amino acid sequence identity” with respect to a referencepolypeptide sequence is defined as the percentage of amino acid residuesin a candidate sequence that are identical with the amino acid residuesin the reference polypeptide sequence, after aligning the sequences andintroducing gaps, if necessary, to achieve the maximum percent sequenceidentity, and not considering any conservative substitutions as part ofthe sequence identity. Alignment for purposes of determining percentamino acid sequence identity can be achieved in various ways that arewithin the skill in the art, for instance, using publicly availablecomputer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR)software. Those skilled in the art can determine appropriate parametersfor aligning sequences, including any algorithms needed to achievemaximal alignment over the full length of the sequences being compared.For purposes herein, however, % amino acid sequence identity values aregenerated using the sequence comparison computer program ALIGN-2. TheALIGN-2 sequence comparison computer program was authored by Genentech,Inc., and the source code has been filed with user documentation in theU.S. Copyright Office, Washington D.C., 20559, where it is registeredunder U.S. Copyright Registration No. TXU510087. The ALIGN-2 program ispublicly available from Genentech, Inc., South San Francisco, Calif., ormay be compiled from the source code. The ALIGN-2 program should becompiled for use on a UNIX operating system, including digital UNIXV4.0D. All sequence comparison parameters are set by the ALIGN-2 programand do not vary.

In situations where ALIGN-2 is employed for amino acid sequencecomparisons, the % amino acid sequence identity of a given amino acidsequence A to, with, or against a given amino acid sequence B (which canalternatively be phrased as a given amino acid sequence A that has orcomprises a certain % amino acid sequence identity to, with, or againsta given amino acid sequence B) is calculated as follows:100 times the fraction X/Ywhere X is the number of amino acid residues scored as identical matchesby the sequence alignment program ALIGN-2 in that program's alignment ofA and B, and where Y is the total number of amino acid residues in B. Itwill be appreciated that where the length of amino acid sequence A isnot equal to the length of amino acid sequence B, the % amino acidsequence identity of A to B will not equal the % amino acid sequenceidentity of B to A. Unless specifically stated otherwise, all % aminoacid sequence identity values used herein are obtained as described inthe immediately preceding paragraph using the ALIGN-2 computer program.

The term “least squares” when used herein refers to the use of leastsquares method which minimizes the sum of the squares of differencebetween each observed value and its estimated value (Plackett, R. L.Biometricka, 59: 239-251 (1972)). The least squares mean presentedherein was an estimate of the mean DDAF change from baseline in GA areabased on a linear mixed effect model (Garret Fitzmaurice, Nan Laird,James Ware, Applied Longitudinal Analysis, 2^(nd) edition, Chapter 8,Publisher (John Wiley & Sons) (August 2011)) which was used to fit therelationship between change in GA area vs. baseline GA lesion size(continuous), baseline GA lesion size category (<4DA vs.≥4DA), time,treatment, and time-by-treatment interaction. See FIGS. 5 and 6.

The term “pharmaceutical formulation” refers to a preparation which isin such form as to permit the biological activity of an activeingredient contained therein to be effective, and which contains noadditional components which are unacceptably toxic to a subject to whichthe formulation would be administered.

A “pharmaceutically acceptable carrier” refers to an ingredient in apharmaceutical formulation, other than an active ingredient, which isnontoxic to a subject. A pharmaceutically acceptable carrier includes,but is not limited to, a buffer, excipient, stabilizer, or preservative.

A “neutralizing antibody” is an antibody molecule which is able toeliminate or significantly reduce an effector function of a targetantigen to which it binds. Accordingly, a “neutralizing” anti-factor Dantibody, or antigen-binding fragment thereof is capable of eliminatingor significantly reducing an effector function, such as alternativecomplement activity, of factor D.

An exemplary assay is one that monitors the ability of an anti-factor Dantibody, or antigen-binding fragment thereof to neutralize alternativecomplement activity of factor D. See, for example, the hemolyticinhibition assay as described in PCT/US2007/083172, published on May 8,2008, whereby neutralization is measured by the ability of a candidateantibody to inhibit rabbit red blood cell hemolysis using Clq-depletedhuman serum as complement source.

Alternatively, the ability of the anti-factor D antibodies to neutralizethe elicitation of a cellular response by factor D may be tested by C3Fluid Phase Convertase Assay, as described by Wiesmann et al., Nature,444: 217-220 (2006)).

“Significant” reduction means at least about 60%, or at least about 70%,preferably at least about 75%, more preferably at least about 80%, evenmore preferably at least about 85%, still more preferably at least about90%, still more preferably at least about 95%, most preferably at leastabout 99% reduction of an effector function of the target antigen (e.g.factor D), such as alternative complement activity. Preferably, the“neutralizing” antibodies as defined herein will be capable ofneutralizing at least about 60%, or at least about 70%, preferably atleast about 75%, more preferably at least about 80%, even morepreferably at least about 85%, still more preferably at least about 90%,still more preferably at least about 95%, most preferably at least about99% of the anti-alternative pathway activity of factor D, as determinedby the hemolytic assay of PCT/US2007/083172, published on May 8, 2008.

A “subject” or “patient” herein is a human subject or patient.Generally, such subject or patient is eligible for treatment forgeographic atrophy. In one embodiment, such eligible subject or patientis one that is experiencing or has experienced one or more signs,symptoms, or other indicators of geographic atrophy or has beendiagnosed with geographic atrophy, whether, for example, newlydiagnosed, previously diagnosed or is at risk for developing geographicatrophy. In another embodiment, the patient to be treated can bescreened using an assay to detect the presence of SNPs associated withAMD. A “stable” formulation is one in which the protein thereinessentially retains its physical stability and/or chemical stabilityand/or biological activity upon storage. Preferably, the formulationessentially retains its physical and chemical stability, as well as itsbiological activity upon storage. The storage period is generallyselected based on the intended shelf-life of the formulation. Variousanalytical techniques for measuring protein stability are available inthe art and are reviewed in Peptide and Protein Drug Delivery, 247-301,Vincent Lee Ed., Marcel Dekker, Inc., New York, N.Y., Pubs. (1991) andJones, A. Adv. Drug Delivery Rev. 10: 29-90 (1993), for example.Stability can be measured at a selected temperature for a selected timeperiod. Preferably, the formulation is stable at about 40° C. for atleast about 2-4 weeks, and/or stable at about 5° C. and/or 15° C. for atleast 3 months, and/or stable at about −20° C. for at least 3 months orat least 1, 2, 3, or 4 years. Furthermore, the formulation is preferablystable following freezing (to, e.g., −70° C.) and thawing of theformulation, for example following 1, 2 or 3 cycles of freezing andthawing. Stability can be evaluated qualitatively and/or quantitativelyin a variety of different ways, including evaluation of aggregateformation (for example using size exclusion chromatography, by measuringturbidity, and/or by visual inspection); by assessing chargeheterogeneity using cation exchange chromatography or capillary zoneelectrophoresis; amino-terminal or carboxy-terminal sequence analysis;mass spectrometric analysis; SDS-PAGE analysis to compare reduced andintact antibody; peptide map (for example tryptic or LYS-C) analysis;evaluating biological activity or antigen binding function of theantibody; etc. Instability may involve any one or more of: aggregation,deamidation (e.g. Asn deamidation), oxidation (e.g. Met oxidation),isomerization (e.g. Asp isomerization),clipping/hydrolysis/fragmentation (e.g. hinge region fragmentation),succinimide formation, unpaired cysteine(s), N-terminal extension,C-terminal processing, glycosylation differences, etc.

A “histidine buffer” is a buffer comprising histidine ions. Examples ofhistidine buffers include histidine chloride, histidine acetate,histidine phosphate, histidine sulfate. The preferred histidine bufferidentified in the examples herein was found to be histidine chloride. Inone embodiment, the histidine chloride buffer is prepared by titratingL-histidine (free base, solid) with hydrochloric acid (liquid). Inanother embodiment, the histidine buffer is prepared by a mixture ofhistidine and histidine-hydrochloride salt to achieve the desired pH.Preferably, the histidine buffer or histidine chloride buffer is at pH5.0 to 6.0, preferably pH 5.2 to 5.8.

A “saccharide” herein comprises the general composition (CH₂O)n andderivatives thereof, including monosaccharides, disaccharides,trisaccharides, polysaccharides, sugar alcohols, reducing sugars,nonreducing sugars, etc. Examples of saccharides herein include glucose,sucrose, trehalose, lactose, fructose, maltose, dextran, glycerin,dextran, erythritol, glycerol, arabitol, sylitol, sorbitol, mannitol,mellibiose, melezitose, raffinose, mannotriose, stachyose, maltose,lactulose, maltulose, glucitol, maltitol, lactitol, iso-maltulose, etc.

Herein, a “surfactant” refers to a surface-active agent, preferably anonionic surfactant. Examples of surfactants herein include polysorbate(for example, polysorbate 20 and, polysorbate 80); poloxamer (e.g.poloxamer 188); Triton; sodium dodecyl sulfate (SDS); sodium laurelsulfate; sodium octyl glycoside; lauryl-, myristyl-, linoleyl-, orstearyl-sulfobetaine; lauryl-, myristyl-, linoleyl- orstearyl-sarcosine; linoleyl-, myristyl-, or cetyl-betaine;lauroamidopropyl-, cocamidopropyl-, linoleamidopropyl-,myristamidopropyl-, paImidopropyl-, or isostearamidopropyl-betaine (e.g.lauroamidopropyl); myristamidopropyl-, paImidopropyl-, orisostearamidopropyl-dimethylamine; sodium methyl cocoyl-, or disodiummethyl oleyl-taurate; and the MONAQUAT™ series (Mona Industries, Inc.,Paterson, N.J.); polyethyl glycol, polypropyl glycol, and copolymers ofethylene and propylene glycol (e.g. Pluronics, PF68 etc); etc. Thepreferred surfactant herein is polysorbate 20.

Diagnosis of GA may be made based on clinical history, clinicalexamination, and established imaging modalities.

“Treatment” of a subject herein refers to both therapeutic treatment andprophylactic or preventative measures. Those in need of treatmentinclude those already with the GA as well as those in which the GA is tobe prevented. Hence, the subject may have been diagnosed as having theGA or may be predisposed or susceptible to the GA.

A “symptom” of GA is any morbid phenomenon or departure from the normalin structure, function, or sensation, experienced by the subject andindicative of disease.

The expression “effective amount” refers to an amount of the antibodythat is effective for preventing, ameliorating, or treating the GA.

“Antibody exposure” refers to contact with or exposure to the antibodyherein in one or more doses administered over a period of time of about1 day to about 5 weeks. The doses may be given at one time or at a fixedor irregular time intervals over this period of exposure, such as, forexample, one dose weekly for four weeks or two doses separated by a timeinterval of about 13-17 days. Initial and later antibody exposures areseparated in time from each other as described in detail herein.

A “factor D inhibitor” herein is an agent that inhibits, to some extent,a biological function of factor D, generally through binding to factor Dand neutralizing its activity. Examples of factor D inhibitorsspecifically contemplated herein are lampalizumab.

A “package insert” is used to refer to instructions customarily includedin commercial packages of therapeutic products, that contain informationabout the indications, usage, dosage, administration, contraindications,other therapeutic products to be combined with the packaged product,and/or warnings concerning the use of such therapeutic products, etc.

An exposure not being administered or provided until a certain time“from the initial exposure” or from any prior exposure means that thetime for the second or later exposure is measured from the time any ofthe doses from the prior exposure were administered, if more than onedose was administered in that exposure. For example, when two doses areadministered in an initial exposure, the second exposure is not givenuntil at least about 16-54 weeks as measured from the time the first orthe second dose was administered within that prior exposure. Similarly,when three doses are administered, the second exposure may be measuredfrom the time of the first, second, or third dose within the priorexposure. Preferably, “from the initial exposure” is measured from thetime of the first dose.

A “medicament” is an active drug to treat the geographic atrophy or itssymptoms or side effects.

The term “administering” as used herein is used in the broadest senseand inter alia encompasses enteral, topical administration and“parenteral administration”. “Parenteral administration” and“administered parenterally” as used herein mean modes of administrationother than enteral and topical administration, usually by injection, andinclude, without limitation, intravenous, intramuscular, intraarterial,intrathecal, intracapsular, intraorbital, intracardiac, intradermal,intraperitoneal, transtracheal, subcutaneous, subcuticular,intraarticular, subcapsular, subarachnoid, intraspinal, epidural,intrasternal injection, infusion, ocular, intraocular, intravitreal,juxtascleral, subtenon and superchoroidal. “IVT or ITV” when used hereinrefers to intravitreal.

The term “assessing AMD” is used to indicate that the method accordingto the present invention will aid a medical professional including,e.g., a physician to assess whether an individual is at risk ofdeveloping intermediate or advanced AMD or prognosing to intermediate oradvanced AMD. The presence of a risk allele for CFI, CFH, C3, C2 or CFBin the sample indicates that the individual is at risk of developingintermediate or advanced AMD or prognosing to advanced AMD.

Results from prognostic tests may be combined with other test results todiagnose progression to more advanced AMD. In some embodiments, theresults from predisposition analyses may be combined with other testresults, epidemiologic or genetic in nature, indicative of progressionto more advanced AMD. In these embodiments, the combination of theprognostic test results with other test results can be probative orprogression to more advanced AMD, and the combination can be utilized asan AMD diagnostic.

The term “progression” as used herein refers to the worsening of adisease over time. The “progression rate” or “rate of progression” of adisease refers to how fast or slow a disease develops over time in apatient diagnosed with the disease. The disease is often chronic and thetime frame can be weeks, months or years. The progression rate of adisease can be represented by measurable changes over time of particularcharacteristics of the disease. For example, the progression rate of apatient with GA can be represented by the growth rate of GA lesion areafrom baseline to month 18 as measured by a standard imaging method suchas fundus autofluorescence (FAF) or color fundus photography (CFP). Apatient carrying particular genetic trait is said to have, or morelikely to have, “increased progression rate” if her disease stateprogresses faster than those patients without such genetic trait. On theother hand, a patient responding to a therapy is said to have, or morelikely to have, “decreased progression rate” if her disease progressionslows down after the therapy, when compared to her disease state priorto the treatment or to other patients without the treatment.

“More likely to respond” as used herein refers to patients that are mostlikely to demonstrate a slowing down or prevention of progression ofAMD. With regard to GA, “more likely to respond” refers to patients thatare most likely to demonstrate a reduction in loss of GA area by FAF orCFP with treatment. With regard to intermediate AMD, “more likely torespond” refers to patients that are more likely to demonstrate aslowing of progression to advanced AMD. With regard to early AMD, “morelikely to respond” refers to patients that are more likely todemonstrate a slowing of progression to intermediate AMD. The phrase“responsive to” in the context of the present invention indicates that apatient suffering from, being suspected to suffer or being prone tosuffer from, or diagnosed with a disorder as described herein, shows aresponse to anti-factor D treatment.

An “individual” or “subject” is a mammal. Mammals include, but are notlimited to, domesticated animals (e.g., cows, sheep, cats, dogs andhorses, primates (e.g., humans and non-human primates such as monkeys,rabbits, and rodents (e.g. mice and rats). In certain embodiments, theindividual or subject is a human.

A “patient” or “subject” herein is any single human subject eligible fortreatment who is experiencing or has experienced one or more signs,symptoms, or other indicators of AMD. Intended to be included as asubject are any subjects involved in clinical research trials notshowing any clinical sign of disease, or subjects involved inepidemiological studies, or subjects once used as controls. The subjectmay have been previously treated with an anti-factor D antibody, orantigen-binding fragment thereof or another drug, or not so treated. Thesubject may be naïve to an additional drug(s) being used when thetreatment herein is started, i.e., the subject may not have beenpreviously treated with, for example, a therapy other than anti-factor Dat “baseline” (i.e., at a set point in time before the administration ofa first dose of anti-factor D in the treatment method herein, such asthe day of screening the subject before treatment is commenced). Such“naïve” subjects are generally considered to be candidates for treatmentwith such additional drug(s).

The phrase “providing an assessment” as used herein refers to using theinformation or data generated relating to the presence of a risk allelein a sample of a patient to assess AMD in the patient. The informationor data may be in any form, written, oral or electronic. In someembodiments, using the information or data generated includescommunicating, presenting, reporting, storing, sending, transferring,supplying, transmitting, dispensing, or combinations thereof. In someembodiments, communicating, presenting, reporting, storing, sending,transferring, supplying, transmitting, dispensing, or combinationsthereof are performed by a computing device, analyzer unit orcombination thereof. In some further embodiments, communicating,presenting, reporting, storing, sending, transferring, supplying,transmitting, dispensing, or combinations thereof are performed by alaboratory or medical professional. In some embodiments, the informationor data includes an indication that the risk allele is present or absentin the sample. In some embodiments, the information or data includes anindication that the patient is assessed with intermediate or advancedAMD.

The term “sample” refers to a sample of a body fluid, to a sample ofseparated cells or to a sample from a tissue or an organ. Samples ofbody fluids can be obtained by well-known techniques and include,samples of blood, plasma, serum, urine, lymphatic fluid, sputum,ascites, bronchial lavage or any other bodily secretion or derivativethereof. Tissue or organ samples may be obtained from any tissue ororgan by, e.g., biopsy. Separated cells may be obtained from the bodyfluids or the tissues or organs by separating techniques such ascentrifugation or cell sorting. E.g., cell-, tissue- or organ samplesmay be obtained from those cells, tissues or organs which express orproduce the biomarker. The sample may be frozen, fresh, fixed (e.g.formalin fixed), centrifuged, and/or embedded (e.g. paraffin embedded),etc. The cell sample can, of course, be subjected to a variety ofwell-known post-collection preparative and storage techniques (e.g.,nucleic acid and/or protein extraction, fixation, storage, freezing,ultrafiltration, concentration, evaporation, centrifugation, etc.) priorto assessing the amount of the marker in the sample. Likewise, biopsiesmay also be subjected to post-collection preparative and storagetechniques, e.g., fixation. The sample could be taken before treatment,during treatment or post-treatment. The sample may be taken from apatient who is suspected of having, or is diagnosed as having AMD, andhence is likely in need of treatment or from a normal individual who isnot suspected of having any disorder.

The phrase “selecting a patient” or “identifying a patient” as usedherein refers to using the information or data generated relating to thepresence of a risk allele in a sample of a patient to identify or selectthe patient as more likely to benefit to benefit from a treatmentcomprising anti-factor D antibody. The information or data used orgenerated may be in any form, written, oral or electronic. In someembodiments, using the information or data generated includescommunicating, presenting, reporting, storing, sending, transferring,supplying, transmitting, dispensing, or combinations thereof. In someembodiments, communicating, presenting, reporting, storing, sending,transferring, supplying, transmitting, dispensing, or combinationsthereof are performed by a computing device, analyzer unit orcombination thereof. In some further embodiments, communicating,presenting, reporting, storing, sending, transferring, supplying,transmitting, dispensing, or combinations thereof are performed by alaboratory or medical professional. In some embodiments, the informationor data includes an indication that a risk allele is present or absentin the sample. In some embodiments, the information or data includes anindication that the patient is more likely to respond to a therapycomprising anti-factor D.

The phrase “selecting a therapy as used herein refers to using theinformation or data generated relating to the presence of a risk allelein a sample of a patient to identify or selecting a therapy for apatient. In some embodiment the therapy may comprise anti-factor D. Insome embodiments the phrase “identifying/selecting a therapy” includesthe identification of a patient who requires adaptation of an effectiveamount of anti-factor D being administered. In some embodimentsrecommending a treatment includes recommending that the amount ofanti-factor D being administered is adapted. The phrase “recommending atreatment” as used herein also may refer to using the information ordata generated for proposing or selecting a therapy comprisinganti-factor D for a patient identified or selected as more likely torespond to the therapy comprising anti-factor D. The information or dataused or generated may be in any form, written, oral or electronic. Insome embodiments, using the information or data generated includescommunicating, presenting, reporting, storing, sending, transferring,supplying, transmitting, dispensing, or combinations thereof. In someembodiments, communicating, presenting, reporting, storing, sending,transferring, supplying, transmitting, dispensing, or combinationsthereof are performed by a computing device, analyzer unit orcombination thereof. In some further embodiments, communicating,presenting, reporting, storing, sending, transferring, supplying,transmitting, dispensing, or combinations thereof are performed by alaboratory or medical professional. In some embodiments, the informationor data includes an indication that a risk allele is present or absentin the sample. In some embodiments, the information or data includes anindication that a therapy comprising anti-factor D is suitable for thepatient

III. Methods

The present invention provides compositions and methods for thetreatment, prognosis, diagnosis and/or selection of a population of AMDpatients that would be good candidates for treatment with complementinhibitor(s). In one embodiment, the invention provides methods forprognosing progression of a degenerative disease (eg. AMD (including GAand CNV) in a patient, comprising determining the presence of a riskallele in the patient. In one embodiment, the invention provides formethods of treating degenerative diseases (e.g., AMD (including GA andCNV)) in a patient, comprising administering an effective amount of anantibody that binds to factor D, wherein the patient carries a riskallele associated with AMD. In some embodiments, the invention providesmethods of treating degenerative diseases (e.g., AMD (including GA andCNV) in a patient, comprising administering a certain antibody thatbinds to factor D according to a particular dosing regimen. In someembodiments, the invention provides methods of treating degenerativediseases (e.g., AMD (including GA and CNV) in a patient, comprisingadministering an effective amount of an antibody, or antigen-bindingfragment thereof, that binds to factor D, wherein the patient isheterozygous or homozygous for a risk allele associated with adegenerative disease (e.g. AMD (including GA and CNV). In someembodiments, the patient carries a risk allele in one, or all, or acombination of CFH, CFI, C3, C2 and CFB. In one embodiment, the antibodyor antigen-binding fragment thereof is lampalizumab. In one embodiment,the invention provides methods for predicting response of a degenerativedisease patient to treatment with an anti-factor D antibody, orantigen-binding fragment thereof. In one embodiment, the inventionprovides methods for optimizing therapeutic efficacy of treatment of apatient with degenerative disease with an anti-factor D antibody, orantigen-binding fragment thereof.

The present invention is based partly on the use of specific genes(e.g., one or more of complement factor I (CFI), complement factor H(CFH), complement component 2 (C2), complement component 3 (C3) andcomplement factor B (CFB), and combinations thereof) or biomarkers(e.g., SNPs of complement factor I (CFI), complement factor H (CFH),complement component 2 (C2), complement component 3 (C3) and complementfactor B (CFB)) that correlate with efficacy of factor D inhibitors(e.g., an anti-factor D antibody or antigen-binding fragment thereof).Thus, the disclosed methods provide convenient, efficient, andpotentially cost-effective means to obtain data and information usefulin assessing appropriate or effective therapies for treating patients.For example, a sample can be obtained from an AMD patient, and thesample could be examined by various in vitro assays to determine whetherthe expression level of one or more biomarkers is present as compared toa reference sample. In one embodiment, if the patient carries a riskallele-, then the patient is likely to benefit from treatment with atherapy comprising a factor D inhibitor (e.g., an anti-factor Dantibody, or antigen-binding fragment thereof, such as, for example,lampalizumab). Presence of a gene or a biomarker or SNP can bedetermined based on any suitable criterion known in the art, includingbut not limited to mRNA, cDNA, proteins, protein fragments and/or genecopy number.

Analysis of SNPs in a sample can be analyzed in blood, tissue or otherbodily fluids by a number of methodologies, many of which are known inthe art and understood by the skilled artisan, including but not limitedto, DNA sequencing, RNA sequencing, polymerase chain reaction analysisof DNA, polymerase chain reaction analysis of RNA, oligonucleotide basedhybridization, in situ hybridization, oligonucleotide based primerextension, electrophoresis and HPLC. Additional techniques for detectingSNPs include but are not limited to the following techniques: scanningprobe and nanopore DNA sequencing, pyrosequencing, Denaturing GradientGel Electrophoresis (DGGE), Temporal Temperature GradientElectrophoresis (TTGE), Zn(II)-cyclen polyacrylamide gelelectrophoresis, homogeneous fluorescent PCR-based single nucleotidepolymorphism analysis, phosphate-affinity polyacrylamide gelelectrophoresis, high-throughput SNP genotyping platforms, molecularbeacons, 5′ nuclease reaction, Taqman assay, MassArray (single baseprimer extension coupled with matrix-assisted laserdesorption/ionization time-of-flight mass spectrometry), trityl masstags, genotyping platforms (such as the Invader Assay®), single baseprimer extension (SBE) assays, PCR amplification (e.g. PCR amplificationon magnetic nanoparticles (MNPs), restriction enzyme analysis of PCRproducts (RFLP methods), allele-specific PCR, multiple primer extension(MPEX), isothermal smart amplification. (Methods in Molecular Biology,Single Nucleotide Polymorphisms, 2^(nd) edition, editor Anton Komar,Humana Press 2009; Chapters 7-28), PCR amplification of simple sequencelength polymorphisms (SSLPs), ligase chain reaction (LCR), RNase Acleavage, chemical cleavage of heteroduplex DNA, single-strandconformation polymorphism (SSCP) analysis (Warren et al., CurrentProtocol in Human Genetics, Supp 15: 7.4.1-7.4.23 (2001), bead-chipmicroarray (Lambert et al., Current Protocol in Human Genetics, Supp 78:2.9.1-2.9.3 (2013)), single-strand conformation polymorphism (SSCP)analysis, primer single-base extension (SBE) (Deshpande et al., CurrentProtocol in Human Genetics, Supp 34: 13.4.1-13.4.11 (2005)), primerextension assay (Kwok et al., Current Protocol in Human Genetics, Supp39: 2.11.1-2.11.10 (2003). The presence of a SNP may also be inferredfrom analysis of protein based techniques (to examine, for example,levels of protein expression or function), including immunoassay (e.g.ELISA, ELIFA, immunohistochemical and/or Western blot analysis,immunoprecipitation, molecular binding assays, fluorescence activatedcell sorting (FACS) and the like, quantitative blood based assays (asfor example Serum ELISA) in situ hybridization, or functional assaysincluding biochemical enzymatic activity assays or cell based systems,as well as any one of the wide variety of assays that can be performedby gene and/or tissue array analysis. Typical protocols for evaluatingthe status of genes and gene products are found, for example in Ausubelet al. eds., 1995, Current Protocols In Molecular Biology, Units 2(Northern Blotting), 4 (Southern Blotting), 15 (Immunoblotting) and 18(PCR Analysis). Multiplexed immunoassays such as those available fromRules Based Medicine, bead based immunoassays e.g. Luminex, ELISA orMeso Scale Discovery (MSD) may also be used.

One technique that is sensitive and amenable for SNP analysis of theinvention is allele-specific PCR (AS-PCR) described in e.g. U.S. Pat.No. 6,627,402. This technique detects mutations or polymorphisms innucleic acid sequences in the presence of wild-type variants of thesequences. In a successful allele-specific PCR, the desired variant ofthe target nucleic acid is amplified, while the other variants are not,at least not to a detectable level.

One measure of discrimination of an allele-specific PCR is thedifference between Ct values (ΔCt) in the amplification reactionsinvolving the two alleles. Each amplification reaction is characterizedby a “growth curve” or “amplification curve” in the context of a nucleicacid amplification assay is a graph of a function, where an independentvariable is the number of amplification cycles and a dependent variableis an amplification-dependent measurable parameter measured at eachcycle of amplification, such as fluorescence emitted by a fluorophore.Typically, the amplification-dependent measurable parameter is theamount of fluorescence emitted by the probe upon hybridization, or uponthe hydrolysis of the probe by the nuclease activity of the nucleic acidpolymerase, see Holland et al., (1991) Proc. Natl. Acad. Sci.88:7276-7280 and U.S. Pat. No. 5,210,015. A growth curve ischaracterized by a “threshold value” (or Ct value) which is a number ofcycles where a predetermined magnitude of the measurable parameter isachieved. A lower Ct value represents more rapid amplification, whilethe higher Ct value represents slower amplification. In the context ofan allele-specific reaction the difference between Ct values of the twotemplates represents allelic discrimination in the reaction.

In an allele-specific PCR, at least one primer is allele-specific suchthat primer extension occurs only (or preferentially) when the specificvariant of the sequence is present and does not occur (or occurs lessefficiently, i.e. with a substantial ΔCt) when another variant ispresent. Design of successful allele-specific primers is anunpredictable art. While it is routine to design a primer for a knownsequence, no formula exists for designing a primer that can discriminatebetween very similar sequences. The discrimination is especiallychallenging when one or more allele-specific primers targeting one ormore polymorphic sites are present in the same reaction mixture.

Typically, the discriminating nucleotide in the primer, i.e. thenucleotide matching only one variant of the target sequence, is the3′-terminal nucleotide. However, the 3′ terminus of the primer is onlyone of many determinants of specificity. For example, additionalmismatches may also affect discrimination. See U.S. patent applicationSer. No. 12/582,068 filed on Oct. 20, 2009 (published as US20100099110.)Another approach is to include non-natural or modified nucleotides thatalter base pairing between the primer and the target sequence (U.S. Pat.No. 6,001,611, incorporated herein in its entirety by reference.) Thereduced extension kinetics and thus specificity of a primer isinfluenced by many factors including overall sequence context of themismatch and other nucleic acids present in the reaction. The effect ofthese external factors on each additional mismatch as well as of eachadditional non-natural nucleotide either alone or in combination cannotbe predicted. The applicants tested multiple variants of the primers andfound that surprisingly, certain variants are dramatically differentwith respect to their ability to discriminate between closely relatedtarget sequences.

In one embodiment the present invention comprises oligonucleotidesspecific for determining polymorphism in CFI, C2, CFB, C3 or CFH,respectively. In one embodiment, the invention comprisesoligonucleotides selected from SEQ ID NOs: 17-41 (Table 9) as well asvariations at least 90% identical to and having the 3′-terminalnucleotide of said oligonucleotides, for specifically detecting riskalleles in CFI SNP rs4698775, CFH SNP rs1329428 and C2/CFB SNP rs429608,respectively. As illustrated in Table 9, the mismatches and non-naturalnucleotides typically occur within the 3′-terminal portion of theoligonucleotides used as primers, specifically within 5 penultimatenucleotides. However, some oligonucleotides sharing 90% identity with agiven oligonucleotide also include those having 1, 2 or 3 mismatcheselsewhere in the oligonucleotide, e.g. in the 5′-portion of theoligonucleotide.

In a particular embodiment the presence of polymorphism is detected witha probe. The probe may be labeled with a radioactive, or a chromophore(fluorophore) label, e.g. a label incorporating FAM, JA270, CY5 familydyes, or HEX dyes. As one example of detection using a fluorescentlylabeled probe, the mutation may be detected by real-time polymerasechain reaction (rt-PCR), where hybridization of the probe results inenzymatic digestion of the probe and detection of the resultingfluorescence (TaqMan™ probe method, Holland et al. (1991) P.N.A.S. USA88:7276-7280). Table 9 lists exemplary probes for detecting risk allelesin CFI SNP rs4698775, CFH SNP rs1329428 and C2/CFB SNP rs429608,respectively. Alternatively, the presence of polymorphism and theamplification product may be detected by gel electrophoresis followed bystaining or by blotting and hybridization as described e.g., inSambrook, J. and Russell, D. W. (2001) Molecular Cloning, 3rd ed. CSHLPress, Chapters 5 and 9.

A “fluorescent dye” or a “fluorophore” is a compound or a moietyattached for example, to a nucleic acid, which is capable of emittinglight radiation when excited by a light of a suitable wavelength.Typical fluorescent dyes include rhodamine dyes, cyanine dyes,fluorescein dyes and BODIPY® dyes. A fluorophore is a fluorescentchromophore. “FRET” or “fluorescent resonance energy transfer” or“Foerster resonance energy transfer” is a transfer of energy between atleast two chromophores, a donor chromophore and an acceptor chromophore(referred to as a quencher). The donor typically transfers the energy tothe acceptor when the donor is excited by light radiation with asuitable wavelength. When the acceptor is a “dark” quencher, itdissipates the transferred energy in a form other than light. Commonlyused dark quenchers are BlackHole Quenchers™ (BHQ), BiosearchTechnologies, Inc. (Novato, Calif.), Iowa Black™, Integrated DNA Tech.,Inc. (Coralville, Iowa), BlackBerry™ Quencher 650 (BBQ-650), Berry &Assoc., (Dexter, Mich.). Commonly used donor-quencher pairs include theFAM-BHQ pair, the CY5-BHQ pair and the HEX-BHQ pair.”

A sample comprising a biomarker or SNP can be obtained by methods wellknown in the art. See under Definitions. In addition, the progress oftherapy can be monitored more easily by testing such body samples forSNPs.

Genotyping arrays may be used to analyze DNA or RNA to detect thepresence of SNPs or other genetic based mechanisms. One such example isthe Illumina based array technology which is a commercially availablemicroarray system which comprises >700K loci. (Oliphant et al.,Biotechniques, Supp: 56-8, 60-1 (2002)) and is a common method used forDNA and RNA analysis (e.g. identification of SNPs in nucleic acidsamples). The Illumina microarray technology utilizes 3-micron silicabeads that self assemble in microwells on either of two substrates:fiber optic bundles or planar silica slides. Each bead is covered withhundreds of thousands of copies of specific oligonucleotides that act asthe capture sequences.

Expression of a selected gene or biomarker in a tissue or cell samplemay also be examined by way of functional or activity-based assays. Forinstance, if the biomarker is an enzyme, one may conduct assays known inthe art to determine or detect the presence of the given enzymaticactivity in the tissue or cell sample.

The SNP status of a patient based on the test results may be provided ina report. The report may be in any form of written materials (e.g., inpaper or digital form, or on internet) or oral presentation(s) (e.g.,either in person (live) or as recorded). The report may furtherindicates to a health professional (e.g., a physician) that the patientmay benefit from or is likely to respond to an factor D inhibitortreatment.

The kits of the invention have a number of embodiments. In certainembodiments, a kit comprises a container, a label on said container, anda composition contained within said container; wherein the compositionincludes one or more primary antibodies that bind to one or more targetpolypeptide sequences corresponding to an autoantibody to a SNP, thelabel on the container indicating that the composition can be used toevaluate the presence of one or more target proteins in at least onetype of mammalian cell, and instructions for using the antibodies forevaluating the presence of one or more target proteins in at least onetype of mammalian cell. The kit can further comprise a set ofinstructions and materials for preparing a tissue sample and applyingantibody and probe to the same section of a tissue sample. The kit mayinclude both a primary and secondary antibody, wherein the secondaryantibody is conjugated to a label, e.g., an enzymatic label.

In one embodiment, the subject has never been previously treated withdrug(s), such as immunosuppressive agent(s), to treat AMD and/or hasnever been previously treated with an antibody or antigen-bindingfragment thereof to factor D. In another embodiment, the subject hasbeen previously treated with drug(s) to treat the degenerative diseaseand/or has been previously treated with such antibody. In anotherembodiment, the anti-factor D antibody or antigen-binding fragmentthereof is the only medicament administered to the subject to treat thedegenerative disease. In another embodiment, the anti-factor D antibodyor antigen-binding fragment thereof is one of the medicaments used totreat AMD.

The antibody is administered by any suitable means, includingparenteral, topical, subcutaneous, intraperitoneal, intrapulmonary,intranasal, intralesional and/or intravitreal administration. Parenteralinfusions include intramuscular, intravenous, intraarterial,intraperitoneal, or subcutaneous administration. Intrathecaladministration is also contemplated. In addition, the antibody maysuitably be administered by pulse infusion, e.g., with declining dosesof the antibody. Preferably, the dosing is given intravenously orsubcutaneously, and more preferably by intravenous infusion(s). Eachexposure may be provided using the same or a different administrationmeans. In one embodiment, each exposure is by IVT administration.

One may administer a second medicament with the anti-factor D antibodyor antigen-binding fragment thereof, such as an VEGF antagonist orantibody.

For instance, the antibody may be combined with an anti-VEGF drug suchas (AVASTIN (bevacizumab) or LUCENTIS (ranibizumab)) or another factor Dantagonist/antibody or antigen-binding fragment thereof.

More specific examples of such second medicaments, if the anti-factor Dantibody or antigen-binding fragment thereof is called the firstmedicament, include a VEGF antagonist or antibody.

These second medicaments are generally used in the same dosages and withadministration routes as used hereinbefore or about from 1 to 99% of theheretofore-employed dosages. If such second medicaments are used at all,preferably, they are used in lower amounts than if the anti-factor Dantibody or antigen-binding fragment thereof were not present,especially in subsequent dosings beyond the initial dosing withantibody, so as to eliminate or reduce side effects caused thereby.

Where a second medicament is administered in an effective amount with anantibody exposure, it may be administered with any exposure, forexample, only with one exposure, or with more than one exposure. In oneembodiment, the second medicament is administered with the initialexposure. In another embodiment, the second medicament is administeredwith the initial and second exposures. In a still further embodiment,the second medicament is administered with all exposures.

The combined administration includes co-administration (concurrentadministration), using separate formulations or a single pharmaceuticalformulation, and consecutive administration in either order, whereinpreferably there is a time period while both (or all) active agentssimultaneously exert their biological activities. In a preferredembodiment, after the initial exposure, the amount of such agent isreduced or eliminated so as to reduce the exposure of the subject to anagent with side effects such as prednisone and cyclophosphamide,especially when the agent is a corticosteroid. In another embodiment,the amount of the second medicament is not reduced or eliminated.

IV. Antibodies Directed to a Factor D Antibody or Antigen-BindingFragment Thereof

Any factor D antibodies or fragments thereof known in the art may beused in the methods described herein. For example, in one embodiment,the anti-factor D antibodies that may be used in the invention are anyof those disclosed in U.S. Pat. No. 8,067,002 or U.S. Pat. No.8,273,352, and may further include chimeric, humanized, or humanversions of these antibodies (if not already a chimeric, humanized, orhuman version), and may further include fragments or derivativesthereof.

In some embodiments, the anti-human factor D monoclonal antibody orantigen-binding fragment thereof binds to and neutralizes a biologicalactivity of at least human factor D. In certain embodiments, the humanfactor D monoclonal antibody or antigen-binding fragment thereof cansignificantly reduce or eliminate a biological activity of the humanfactor D in question. In one embodiment, the human factor D monoclonalantibody or antigen-binding fragment thereof is capable of neutralizingat least 60%, or at least 70%, preferably at least 75%, more preferablyat least 80%, even more preferably at least 85%, still more preferablyat least 90%, still more preferably at least 95%, most preferably atleast 99% of a biological activity of the subject human factor D.Binding and neutralization assays are well known in the art. See, e.g.,U.S. Pat. No. 7,087,726 for assays useful in screening for antibodieshaving the desired binding and neutralization properties.

In certain embodiments, the anti-factor D antibody, or antigen-bindingfragment thereof is capable of reducing alternative pathway hemolysis,due to factor D, by at least about 60%, or at least 70%, preferably atleast 75%, more preferably at least 80%, even more preferably at least85%, still more preferably at least 90%, still more preferably at least95%, most preferably at least 99% as determined by an alternativepathway hemolysis assay.

In some embodiments, the anti-factor D monoclonal antibody comprises thefollowing HVRs

(a) L1 of the formula (SEQ ID NO: 1) ITSTDIDDDMN; (b) L2 of the formula(SEQ ID NO: 2) GGNTLRP; and (c) L3 of the formula (SEQ ID NO: 3)LQSDSLPYT; and/or (d) H1 of the formula (SEQ ID NO: 4) GYTFTNYGMN;(e) H2 of the formula (SEQ ID NO: 5) WINTYTGETTYADDFKG; and(f) H3 of the formula (SEQ ID NO: 6) EGGVNN.

In certain embodiments, the anti-human factor D monoclonal antibodycomprises in its heavy and light chain variable domain amino acidsequences of

-   -   EVQLVQSGPELKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMG        WINTYTGETTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCEREGG        VNNWGQGTLVTVSS (SEQ ID NO:7) and    -   DIQVTQSPSSLSASVGDRVTITCITSTDIDDDMNWYQQKPGKVPKLLISGGNTL        RPGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCLQSDSLPYTFGQGTKVEIK (SEQ ID        NO:8), respectively.

In certain embodiments, the anti-factor D antibody comprises thesequences of SEQ ID NO:15 and SEQ ID NO:16 as shown below, wherein 238-1refers to the specific humanized anti-factor D Fab described in U.S.Pat. No. 8,273,352:

Heavy chain sequence of humanized anti-factor D Fab (238-1):

(SEQ ID NO: 15) EVQLVQSGPELKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGETTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCEREGGVNNWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT

Light chain sequence of humanized anti-Factor D Fab (238-1):

(SEQ ID NO: 16) DIQVTQSPSSLSASVGDRVTITCITSTDIDDDMNWYQQKPGKVPKLLISGGNTLRPGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCLQSDSLPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEV THQGLSSPVTKSFNRGEC

In another embodiment, the antibody comprises the variable regionsequences of SEQ ID NO:15 and SEQ ID NO:16. In another embodiment, theantibody comprises the HVR sequences of SEQ ID NO:15 and SEQ ID NO:16.In another embodiment, the antibody comprises the HVR sequences that are95% or more identical to the HVR sequences of SEQ ID NO: 15 and SEQ IDNO: 16 and/or an antibody comprising HVR sequences that are 95%identical to the HVR sequences of SEQ ID NO:15 and SEQ ID NO:16.

In any of the above embodiments, an anti-factor D antibody can behumanized. In one embodiment, an anti-factor D antibody comprises HVRsas in any of the above embodiments, and further comprises an acceptorhuman framework, e.g. a human immunoglobulin framework or a humanconsensus framework.

In another aspect, an anti-factor D antibody comprises a heavy chainvariable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acidsequence of SEQ ID NO: 15. In certain embodiments, a VH sequence havingat least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identitycontains substitutions (e.g., conservative substitutions), insertions,or deletions relative to the reference sequence, but a factor D antibodycomprising that sequence retains the ability to bind to factor D. Incertain embodiments, a total of 1 to 10 amino acids have beensubstituted, inserted and/or deleted in SEQ ID NO:15. In certainembodiments, substitutions, insertions, or deletions occur in regionsoutside the HVRs (i.e., in the FRs). Optionally, the anti-factor Dantibody comprises the VH sequence in SEQ ID NO:15, includingpost-translational modifications of that sequence.

In another aspect, an anti-factor D antibody comprises a light chainvariable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acidsequence of SEQ ID NO: 16. In certain embodiments, a VL sequence havingat least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identitycontains substitutions (e.g., conservative substitutions), insertions,or deletions relative to the reference sequence, but a factor D antibodycomprising that sequence retains the ability to bind to factor D. Incertain embodiments, a total of 1 to 10 amino acids have beensubstituted, inserted and/or deleted in SEQ ID NO:16. In certainembodiments, substitutions, insertions, or deletions occur in regionsoutside the HVRs (i.e., in the FRs). Optionally, the anti-factor Dantibody comprises the VL sequence in SEQ ID NO:16, includingpost-translational modifications of that sequence.

In another aspect, a factor D antibody is provided, wherein the antibodycomprises a VH as in any of the embodiments provided above, and a VL asin any of the embodiments provided above.

In a further aspect, the invention provides an antibody that binds tothe same epitope as another factor D antibody. In one embodiment, theinvention provides an antibody that binds to the same epitope as afactor D antibody provided herein. In one embodiment, the anti-factor Dantibody binds to the same epitope on factor D bound by the anti-factorD antibody comprising a light chain comprising HVR-L1 comprising theamino acid sequence ITSTDIDDDMN (SEQ ID NO:1), HVR-L2 comprising theamino acid sequence GGNTLRP (SEQ ID NO:2), and HVR-L3 comprising theamino acid sequence LQSDSLPYT (SEQ ID NO: 3); and/or a heavy chaincomprising HVR-H1 comprising the amino acid sequence GYTFTNYGMN (SEQ IDNO: 4), HVR-H2 comprising the amino acid sequence WINTYTGETTYADDFKG (SEQID NO:5), and HVR-H3 comprising the amino acid sequence EGGVNN (SEQ IDNO:6). In one embodiment, the anti-factor D antibody binds to the sameepitope on factor D bound by the antibody comprising a heavy chainvariable region sequence of at least 95% sequence identity to the aminoacid sequence of SEQ ID NO:7; and/or a light chain variable regionsequence of at least 95% sequence identity to the amino acid sequence ofSEQ ID NO:8. In one embodiment, the anti-factor D antibody binds to thesame epitope on factor D bound by the antibody comprising a heavy chainvariable region comprising the amino acid sequence of SEQ ID NO:7;and/or a light chain variable region comprising the amino acid sequenceof SEQ ID NO:8. In one embodiment, the anti-factor D antibody binds tothe same epitope on factor D bound by the antibody comprising a heavychain sequence of at least 95% sequence identity to the amino acidsequence of SEQ ID NO:15; and/or a light chain sequence of at least 95%sequence identity to the amino acid sequence of SEQ ID NO:16. In oneembodiment, the anti-factor D antibody binds to the same epitope onfactor D bound by the antibody comprising a heavy chain comprising theamino acid sequence of SEQ ID NO:15; and/or a light chain comprising theamino acid sequence of SEQ ID NO:16. In one embodiment, the anti-factorD antibody binds to the same epitope on factor D bound by lampalizumabhaving CAS registration number 1278466-20-8.

In a further aspect, the invention provides an antibody thatcompetitively inhibits the binding of an anti-factor D antibody to itsrespective antigenic epitope. For example, in certain embodiments,anti-factor D antibody competitively inhibits the binding of theanti-factor D antibody comprising a light chain comprising HVR-L1comprising the amino acid sequence ITSTDIDDDMN (SEQ ID NO:1), HVR-L2comprising the amino acid sequence GGNTLRP (SEQ ID NO:2), and HVR-L3comprising the amino acid sequence LQSDSLPYT (SEQ ID NO: 3); and/or aheavy chain comprising HVR-H1 comprising the amino acid sequenceGYTFTNYGMN (SEQ ID NO: 4), HVR-H2 comprising the amino acid sequenceWINTYTGETTYADDFKG (SEQ ID NO:5), and HVR-H3 comprising the amino acidsequence EGGVNN (SEQ ID NO:6) to its respective antigenic epitope. Inone embodiment, the anti-factor D antibody competitively inhibits thebinding of the antibody comprising a heavy chain variable regionsequence of at least 95% sequence identity to the amino acid sequence ofSEQ ID NO:7; and/or a light chain variable region sequence of at least95% sequence identity to the amino acid sequence of SEQ ID NO:8 to itsrespective antigenic epitope. In one embodiment, the anti-factor Dantibody competitively inhibits the binding of the antibody comprising aheavy chain variable region comprising the amino acid sequence of SEQ IDNO:7; and/or a light chain variable region comprising the amino acidsequence of SEQ ID NO:8 to its respective antigenic epitope. In oneembodiment, the anti-factor D antibody binds to the same epitope onfactor D bound by the antibody comprising a heavy chain sequence of atleast 95% sequence identity to the amino acid sequence of SEQ ID NO:15;and/or a light chain sequence of at least 95% sequence identity to theamino acid sequence of SEQ ID NO:16. In one embodiment, the anti-factorD antibody binds to the same epitope on factor D bound by the antibodycomprising a heavy chain comprising the amino acid sequence of SEQ IDNO:15; and/or a light chain comprising the amino acid sequence of SEQ IDNO:16. In one embodiment, the anti-factor D antibody competitivelyinhibits the binding of lampalizumab having CAS registration number1278466-20-8 to its respective antigenic epitope.

In a further aspect of the invention, a factor D antibody according toany of the above embodiments is a monoclonal antibody, including achimeric, humanized or human antibody. In one embodiment, a factor Dantibody is an antibody fragment, e.g., a Fv, Fab, Fab′, scFv, diabody,or F(ab′)2 fragment. In another embodiment, the antibody is a fulllength antibody, e.g., an intact IgG1 or IgG4 antibody or other antibodyclass or isotype as defined herein. In another embodiment, the antibodyis a bispecific antibody

In a further aspect, a Factor D antibody according to any of the aboveembodiments may incorporate any of the features, singly or incombination, as described in this Section IV and Section V below.

In some embodiments, the anti-factor D monoclonal antibody orantigen-binding fragment thereof has an amino acid sequence that isidentical to the anti-human factor D monoclonal antibody having thenon-proprietary name adopted by the USAN Council designated asLampalizumab. In other embodiments, the anti-human factor D monoclonalantibody or antigen-binding fragment thereof has an amino acid sequenceidentity that is at least 80%, at least 85%, at least 90%, at least 95%,at least 96%, at least 97%, at least 98%, or at least 99% toLampalizumab. See U.S. Pat. No. 8,067,002 or U.S. Pat. No. 8,273,352. Incertain embodiments, the anti-human factor D monoclonal antibody isLampalizumab. In some embodiments, the anti-human factor D monoclonalantibody has an amino acid sequence as disclosed in CAS Registry Number1278466-20-8.

In some embodiments, the anti-human factor D monoclonal antibodycomprises the HVRs encoded by the following sequences:

(a) L1 of the formula (SEQ ID NO: 9) ATTACCAGCACTGATATTGATGATGATATGAAC;(b) L2 of the formula (SEQ ID NO: 10) GGAGGCAATACTCTTCGTCCT;(c) L3 of the formula (SEQ ID NO: 11) TTGCAAAGTGATTCTTTGCCGTACACG;(d) H1 of the formula (SEQ ID NO: 12) GGATACACCTTCACTAACTATGGAATGAAC;(e) H2 of the formula (SEQ ID NO: 13)TGGATTAACACCTACACTGGAGAGACAACATATGCTGACGACTTCAAGG GA; and(f) H3 of the formula (SEQ ID NO: 14) GAGGGGGGGGTTAATAAC.

V. Production of Antibodies

The methods and articles of manufacture of the present invention mayuse, or incorporate, an antibody that binds to factor D. Accordingly,methods for generating such antibodies will be described here.

Factor D antigen to be used for production of, or screening for,antibody(ies) may be, e.g., a soluble form of factor D, or a portionthereof, containing the desired epitope. Alternatively, or additionally,cells expressing factor D at their cell surface can be used to generate,or screen for, antibody(ies). Other forms of factor D useful forgenerating antibodies will be apparent to those skilled in the art.

A description follows as to exemplary techniques for the production ofthe antibodies used in accordance with the present invention.

(i) Polyclonal Antibodies

Polyclonal antibodies are preferably raised in animals by multiplesubcutaneous (sc) or intraperitoneal (ip) injections of the relevantantigen and an adjuvant. It may be useful to conjugate the relevantantigen to a protein that is immunogenic in the species to be immunized,e.g., keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin, orsoybean trypsin inhibitor using a bifunctional or derivatizing agent,for example, maleimidobenzoyl sulfosuccinimide ester (conjugationthrough cysteine residues), N-hydroxysuccinimide (through lysineresidues), glutaraldehyde, succinic anhydride, SOCl₂, or R¹N═C═NR, whereR and R¹ are different alkyl groups.

Animals are immunized against the antigen, immunogenic conjugates, orderivatives by combining, e.g., 100 μg or 5 μg of the protein orconjugate (for rabbits or mice, respectively) with 3 volumes of Freund'scomplete adjuvant and injecting the solution intradermally at multiplesites. One month later the animals are boosted with ⅕ to 1/10 theoriginal amount of peptide or conjugate in Freund's complete adjuvant bysubcutaneous injection at multiple sites. Seven to 14 days later theanimals are bled and the serum is assayed for antibody titer. Animalsare boosted until the titer plateaus. Preferably, the animal is boostedwith the conjugate of the same antigen, but conjugated to a differentprotein and/or through a different cross-linking reagent. Conjugatesalso can be made in recombinant cell culture as protein fusions. Also,aggregating agents such as alum are suitably used to enhance the immuneresponse.

(ii) Monoclonal Antibodies

Monoclonal antibodies are obtained from a population of substantiallyhomogeneous antibodies, i.e., the individual antibodies comprising thepopulation are identical and/or bind the same epitope except forpossible variants that arise during production of the monoclonalantibody, such variants generally being present in minor amounts. Thus,the modifier “monoclonal” indicates the character of the antibody as notbeing a mixture of discrete or polyclonal antibodies.

For example, the monoclonal antibodies may be made using the hybridomamethod first described by Kohler et al., Nature, 256:495 (1975), or maybe made by recombinant DNA methods (U.S. Pat. No. 4,816,567).

In the hybridoma method, a mouse or other appropriate host animal, suchas a hamster, is immunized as hereinabove described to elicitlymphocytes that produce or are capable of producing antibodies thatwill specifically bind to the protein used for immunization.Alternatively, lymphocytes may be immunized in vitro. Lymphocytes thenare fused with myeloma cells using a suitable fusing agent, such aspolyethylene glycol, to form a hybridoma cell (Goding, MonoclonalAntibodies: Principles and Practice, pp. 59-103 (Academic Press, 1986)).

The hybridoma cells thus prepared are seeded and grown in a suitableculture medium that preferably contains one or more substances thatinhibit the growth or survival of the unfused, parental myeloma cells.For example, if the parental myeloma cells lack the enzyme hypoxanthineguanine phosphoribosyl transferase (HGPRT or HPRT), the culture mediumfor the hybridomas typically will include hypoxanthine, aminopterin, andthymidine (HAT medium), which substances prevent the growth ofHGPRT-deficient cells.

Preferred myeloma cells are those that fuse efficiently, support stablehigh-level production of antibody by the selected antibody-producingcells, and are sensitive to a medium such as HAT medium. Among these,preferred myeloma cell lines are murine myeloma lines, such as thosederived from MOPC-21 and MPC-11 mouse tumors available from the SalkInstitute Cell Distribution Center, San Diego, Calif. USA, and SP-2 orX63-Ag8-653 cells available from the American Type Culture Collection,Rockville, Md. USA. Human myeloma and mouse-human heteromyeloma celllines also have been described for the production of human monoclonalantibodies (Kozbor, J. Immunol., 133:3001 (1984); Brodeur et al.,Monoclonal Antibody Production Techniques and Applications, pp. 51-63(Marcel Dekker, Inc., New York, 1987)).

Culture medium in which hybridoma cells are growing is assayed forproduction of monoclonal antibodies directed against the antigen.Preferably, the binding specificity of monoclonal antibodies produced byhybridoma cells is determined by immunoprecipitation or by an in vitrobinding assay, such as radioimmunoassay (RIA) or enzyme-linkedimmunoabsorbent assay (ELISA).

The binding affinity of the monoclonal antibody can, for example, bedetermined by the Scatchard analysis of Munson et al., Anal. Biochem.,107:220 (1980).

After hybridoma cells are identified that produce antibodies of thedesired specificity, affinity, and/or activity, the clones may besubcloned by limiting dilution procedures and grown by standard methods(Goding, Monoclonal Antibodies: Principles and Practice, pp. 59-103(Academic Press, 1986)). Suitable culture media for this purposeinclude, for example, D-MEM or RPMI-1640 medium. In addition, thehybridoma cells may be grown in vivo as ascites tumors in an animal.

The monoclonal antibodies secreted by the subclones are suitablyseparated from the culture medium, ascites fluid, or serum byconventional immunoglobulin purification procedures such as, forexample, protein A-SEPHAROSE™ crosslinked agarose, hydroxylapatitechromatography, gel electrophoresis, dialysis, or affinitychromatography.

DNA encoding the monoclonal antibodies is readily isolated and sequencedusing conventional procedures (e.g., by using oligonucleotide probesthat are capable of binding specifically to genes encoding the heavy andlight chains of murine antibodies). The hybridoma cells serve as apreferred source of such DNA. Once isolated, the DNA may be placed intoexpression vectors, which are then transfected into host cells such asE. coli cells, simian COS cells, Chinese Hamster Ovary (CHO) cells, ormyeloma cells that do not otherwise produce immunoglobulin protein, toobtain the synthesis of monoclonal antibodies in the recombinant hostcells. Review articles on recombinant expression in bacteria of DNAencoding the antibody include Skerra et al., Curr. Opinion in Immunol.,5:256-262 (1993) and Pliickthun, Immunol. Revs., 130:151-188 (1992).

In a further embodiment, antibodies or antibody fragments can beisolated from antibody phage libraries generated using the techniquesdescribed in McCafferty et al., Nature, 348:552-554 (1990). Clackson etal., Nature, 352:624-628 (1991) and Marks et al., J. Mol. Biol.,222:581-597 (1991) describe the isolation of murine and humanantibodies, respectively, using phage libraries. Subsequent publicationsdescribe the production of high-affinity (nM range) human antibodies bychain shuffling (Marks et al., Bio/Technology, 10:779-783 (1992)), aswell as combinatorial infection and in vivo recombination as a strategyfor constructing very large phage libraries (Waterhouse et al., Nuc.Acids. Res., 21:2265-2266 (1993)). Thus, these techniques are viablealternatives to traditional monoclonal antibody hybridoma techniques forisolation of monoclonal antibodies.

The DNA also may be modified, for example, by substituting the codingsequence for human heavy- and light-chain constant domains in place ofthe homologous murine sequences (U.S. Pat. No. 4,816,567; Morrison, etal., Proc. Natl. Acad. Sci. USA, 81:6851 (1984)), or by covalentlyjoining to the immunoglobulin-coding sequence all or part of the codingsequence for a non-immunoglobulin polypeptide.

Typically, such non-immunoglobulin polypeptides are substituted for theconstant domains of an antibody, or they are substituted for thevariable domains of one antigen-combining site of an antibody to createa chimeric bivalent antibody comprising one antigen-combining sitehaving specificity for an antigen and another antigen-combining sitehaving specificity for a different antigen.

(iii) Humanized Antibodies

Methods for humanizing non-human antibodies have been described in theart. Preferably, a humanized antibody has one or more amino acidresidues introduced into it from a source that is non-human. Thesenon-human amino acid residues are often referred to as “import”residues, which are typically taken from an “import” variable domain.Humanization can be essentially performed following the method of Winterand co-workers (Jones et al., Nature, 321:522-525 (1986); Riechmann etal., Nature, 332:323-327 (1988); Verhoeyen et al., Science,239:1534-1536 (1988)), by substituting hypervariable-region sequencesfor the corresponding sequences of a human antibody. Accordingly, such“humanized” antibodies are chimeric antibodies (U.S. Pat. No. 4,816,567)wherein substantially less than an intact human variable domain has beensubstituted by the corresponding sequence from a non-human species. Inpractice, humanized antibodies are typically human antibodies in whichsome hypervariable-region residues and possibly some FR residues aresubstituted by residues from analogous sites in rodent antibodies.

The choice of human variable domains, both light and heavy, to be usedin making the humanized antibodies is very important to reduceantigenicity. According to the so-called “best-fit” method, the sequenceof the variable domain of a rodent antibody is screened against theentire library of known human variable-domain sequences. The humansequence that is closest to that of the rodent is then accepted as thehuman framework region (FR) for the humanized antibody (Sims et al., J.Immunol., 151:2296 (1993); Chothia et al., J. Mol. Biol., 196:901(1987)). Another method uses a particular framework region derived fromthe consensus sequence of all human antibodies of a particular subgroupof light- or heavy-chain variable regions. The same framework may beused for several different humanized antibodies (Carter et al., Proc.Natl. Acad. Sci. USA, 89:4285 (1992); Presta et al., J. Immunol.,151:2623 (1993)).

It is further important that antibodies be humanized with retention ofhigh affinity for the antigen and other favorable biological properties.To achieve this goal, according to a preferred method, humanizedantibodies are prepared by a process of analysis of the parentalsequences and various conceptual humanized products usingthree-dimensional models of the parental and humanized sequences.Three-dimensional immunoglobulin models are commonly available and arefamiliar to those skilled in the art. Computer programs are availablethat illustrate and display probable three-dimensional conformationalstructures of selected candidate immunoglobulin sequences. Inspection ofthese displays permits analysis of the likely role of the residues inthe functioning of the candidate immunoglobulin sequence, i.e., theanalysis of residues that influence the ability of the candidateimmunoglobulin to bind its antigen. In this way, FR residues can beselected and combined from the recipient and import sequences so thatthe desired antibody characteristic, such as increased affinity for thetarget antigen(s), is achieved. In general, the hypervariable regionresidues are directly and most substantially involved in influencingantigen binding.

(iv) Human Antibodies

As an alternative to humanization, human antibodies can be generated.For example, it is now possible to produce transgenic animals (e.g.,mice) that are capable, upon immunization, of producing a fullrepertoire of human antibodies in the absence of endogenousimmunoglobulin production. For example, it has been described that thehomozygous deletion of the antibody heavy-chain-joining region (J_(H))gene in chimeric and germ-line mutant mice results in completeinhibition of endogenous antibody production. Transfer of the humangerm-line immunoglobulin gene array in such germ-line mutant mice willresult in the production of human antibodies upon antigen challenge.See, e.g., Jakobovits et al., Proc. Natl. Acad. Sci. USA, 90:2551(1993); Jakobovits et al., Nature, 362:255-258 (1993); Bruggermann etal., Year in Immuno., 7:33 (1993); and U.S. Pat. Nos. 5,591,669,5,589,369 and 5,545,807.

Alternatively, phage-display technology (McCafferty et al., Nature348:552-553 (1990)) can be used to produce human antibodies and antibodyfragments in vitro, from immunoglobulin variable (V)-domain generepertoires from unimmunized donors. According to this technique,antibody V-domain genes are cloned in-frame into either a major or minorcoat-protein gene of a filamentous bacteriophage, such as M13 or fd, anddisplayed as functional antibody fragments on the surface of the phageparticle. Because the filamentous particle contains a single-strandedDNA copy of the phage genome, selections based on the functionalproperties of the antibody also result in selection of the gene encodingthe antibody exhibiting those properties. Thus, the phage mimics some ofthe properties of the B cell. Phage display can be performed in avariety of formats; for their review see, e.g., Johnson, Kevin S, andChiswell, David J., Current Opinion in Structural Biology 3:564-571(1993). Several sources of V-gene segments can be used for phagedisplay. Clackson et al., Nature, 352:624-628 (1991) isolated a diversearray of anti-oxazolone antibodies from a small random combinatoriallibrary of V genes derived from the spleens of immunized mice. Arepertoire of V genes from unimmunized human donors can be constructedand antibodies to a diverse array of antigens (including self-antigens)can be isolated essentially following the techniques described by Markset al., J. Mol. Biol. 222:581-597 (1991), or Griffith et al., EMBO J.12:725-734 (1993). See, also, U.S. Pat. Nos. 5,565,332 and 5,573,905.

Human antibodies may also be generated by in vitro-activated B cells(see U.S. Pat. Nos. 5,567,610 and 5,229,275).

(v) Antibody Fragments

Various techniques have been developed for the production of antibodyfragments. Traditionally, these fragments were derived via proteolyticdigestion of intact antibodies (see, e.g., Morimoto et al., Journal ofBiochemical and Biophysical Methods 24:107-117 (1992) and Brennan etal., Science, 229:81 (1985)). However, these fragments can now beproduced directly by recombinant host cells. For example, the antibodyfragments can be isolated from the antibody phage libraries discussedabove. Alternatively, Fab′-SH fragments can be directly recovered fromE. coli and chemically coupled to form F(ab′)₂ fragments (Carter et al.,Bio/Technology 10:163-167 (1992)). According to another approach,F(ab′)₂ fragments can be isolated directly from recombinant host-cellculture. Other techniques for the production of antibody fragments willbe apparent to the skilled practitioner. In other embodiments, theantibody of choice is a single-chain Fv fragment (scFv). See WO1993/16185 and U.S. Pat. Nos. 5,571,894 and 5,587,458. The antibodyfragment may also be a “linear antibody”, e.g., as described in U.S.Pat. No. 5,641,870. Such linear antibody fragments may be monospecificor bispecific.

(vi) Bispecific Antibodies

Bispecific antibodies are antibodies that have binding specificities forat least two different epitopes. Exemplary bispecific antibodies maybind to two different epitopes of the factor D antigen. Alternatively,an anti-factor D-binding arm may be combined with an arm that binds to atriggering molecule on a leukocyte such as a T-cell receptor molecule(e.g. CD2 or CD3), or Fc receptors for IgG (FcγR), such as FcγRI (CD64),FcγRII (CD32) and FcγRIII (CD16). Bispecific antibodies may also be usedto localize cytotoxic agents. These antibodies possess a factor Dbinding arm and an arm that binds the cytotoxic agent (e.g. saporin,vinca alkaloid, ricin A chain, methotrexate or radioactive isotopehapten). Bispecific antibodies can be prepared as full-length antibodiesor antibody fragments (e.g. F(ab′)₂ bispecific antibodies).

Methods for making bispecific antibodies are known in the art.Traditional production of full-length bispecific antibodies is based onthe coexpression of two immunoglobulin heavy-chain-light-chain pairs,where the two chains have different specificities (Millstein et al.,Nature, 305:537-539 (1983)). Because of the random assortment ofimmunoglobulin heavy and light chains, these hybridomas (quadromas)produce a potential mixture of 10 different antibody molecules, of whichonly one has the correct bispecific structure. Purification of thecorrect molecule, which is usually done by affinity chromatographysteps, is rather cumbersome, and the product yields are low. Similarprocedures are disclosed in WO 1993/08829, and in Traunecker et al.,EMBO J., 10:3655-3659 (1991).

According to a different approach, antibody variable domains with thedesired binding specificities (antibody-antigen combining sites) arefused to immunoglobulin constant-domain sequences. The fusion preferablyis with an immunoglobulin heavy-chain constant domain, comprising atleast part of the hinge, CH2, and CH3 regions. It is preferred to havethe first heavy-chain constant region (CH1), containing the sitenecessary for light-chain binding, present in at least one of thefusions. DNAs encoding the immunoglobulin heavy-chain fusions and, ifdesired, the immunoglobulin light chain, are inserted into separateexpression vectors, and are co-transfected into a suitable hostorganism. This provides for great flexibility in adjusting the mutualproportions of the three polypeptide fragments in embodiments whenunequal ratios of the three polypeptide chains used in the constructionprovide the optimum yields. It is, however, possible to insert thecoding sequences for two or all three polypeptide chains in oneexpression vector when the expression of at least two polypeptide chainsin equal ratios results in high yields or when the ratios are of noparticular significance.

In a preferred embodiment of this approach, the bispecific antibodiesare composed of a hybrid immunoglobulin heavy chain with a first bindingspecificity in one arm, and a hybrid immunoglobulinheavy-chain-light-chain pair (providing a second binding specificity) inthe other arm. It was found that this asymmetric structure facilitatesthe separation of the desired bispecific compound from unwantedimmunoglobulin chain combinations, as the presence of an immunoglobulinlight chain in only one half of the bispecific molecule provides for afacile way of separation. This approach is disclosed in WO 1994/04690.For further details of generating bispecific antibodies, see, forexample, Suresh et al., Methods in Enzymology, 121:210 (1986).

According to another approach described in U.S. Pat. No. 5,731,168, theinterface between a pair of antibody molecules can be engineered tomaximize the percentage of heterodimers that are recovered fromrecombinant cell culture. The preferred interface comprises at least apart of the C_(H)3 domain of an antibody constant domain. In thismethod, one or more small amino acid side chains from the interface ofthe first antibody molecule are replaced with larger side chains (e.g.tyrosine or tryptophan). Compensatory “cavities” of identical or similarsize to the large side chain(s) are created on the interface of thesecond antibody molecule by replacing large amino acid side chains withsmaller ones (e.g. alanine or threonine). This provides a mechanism forincreasing the yield of the heterodimer over other unwanted end-productssuch as homodimers.

Bispecific antibodies include cross-linked or “heteroconjugate”antibodies. For example, one of the antibodies in the heteroconjugatecan be coupled to avidin, the other to biotin. Such antibodies have, forexample, been proposed to target immune system cells to unwanted cells(U.S. Pat. No. 4,676,980), and for treatment of HIV infection (WO1991/00360, WO 1992/200373, and EP 03089). Heteroconjugate antibodiesmay be made using any convenient cross-linking methods. Suitablecross-linking agents are well known in the art, and are disclosed, forexample, in U.S. Pat. No. 4,676,980, along with a number ofcross-linking techniques.

Techniques for generating bispecific antibodies from antibody fragmentshave also been described in the literature. For example, bispecificantibodies can be prepared using chemical linkage. Brennan et al.,Science, 229: 81 (1985) describe a procedure wherein intact antibodiesare proteolytically cleaved to generate F(ab′)₂ fragments. Thesefragments are reduced in the presence of the dithiol complexing agentsodium arsenite to stabilize vicinal dithiols and prevent intermoleculardisulfide formation. The Fab′ fragments generated are then converted tothionitrobenzoate (TNB) derivatives. One of the Fab′-TNB derivatives isthen reconverted to the Fab′-thiol by reduction with mercaptoethylamineand is mixed with an equimolar amount of the other Fab′-TNB derivativeto form the bispecific antibody. The bispecific antibodies produced canbe used as agents for the selective immobilization of enzymes.

Various techniques for making and isolating bispecific antibodyfragments directly from recombinant cell culture have also beendescribed. For example, bispecific antibodies have been produced usingleucine zippers. Kostelny et al., J. Immunol., 148(5):1547-1553 (1992).The leucine zipper peptides from the Fos and Jun proteins were linked tothe Fab′ portions of two different antibodies by gene fusion. Theantibody homodimers were reduced at the hinge region to form monomersand then re-oxidized to form the antibody heterodimers. This method canalso be utilized for the production of antibody homodimers. The“diabody” technology described by Hollinger et al., Proc. Natl. Acad.Sci. USA, 90:6444-6448 (1993) has provided an alternative mechanism formaking bispecific antibody fragments. The fragments comprise aheavy-chain variable domain (V_(H)) connected to a light-chain variabledomain (V_(L)) by a linker that is too short to allow pairing betweenthe two domains on the same chain. Accordingly, the V_(H) and V_(L)domains of one fragment are forced to pair with the complementary V_(L)and V_(H) domains of another fragment, thereby forming twoantigen-binding sites. Another strategy for making bispecific antibodyfragments by the use of single-chain Fv (sFv) dimers has also beenreported. See Gruber et al., J. Immunol., 152:5368 (1994).

Antibodies with more than two valencies are contemplated. For example,trispecific antibodies can be prepared. Tutt et al. J. Immunol. 147: 60(1991).

VI. Conitmates and Other Modifications of the Antibody

The antibody used in the methods or included in the articles ofmanufacture herein is optionally conjugated to a cytotoxic agent. Forinstance, the (factor D) antibody may be conjugated to a drug asdescribed in WO 2004/032828.

Chemotherapeutic agents useful in the generation of suchantibody-cytotoxic agent conjugates have been described above.

Conjugates of an antibody and one or more small-molecule toxins, such asa calicheamicin, a maytansine (U.S. Pat. No. 5,208,020), a trichothene,and CC 1065 are also contemplated herein. In one embodiment of theinvention, the antibody is conjugated to one or more maytansinemolecules (e.g. about 1 to about 10 maytansine molecules per antibodymolecule). Maytansine may, for example, be converted to May-SS-Me, whichmay be reduced to May-SH3 and reacted with modified antibody (Chari etal. Cancer Research 52: 127-131 (1992)) to generate amaytansinoid-antibody conjugate.

Alternatively, the antibody is conjugated to one or more calicheamicinmolecules. The calicheamicin family of antibiotics is capable ofproducing double-stranded DNA breaks at sub-picomolar concentrations.Structural analogues of calicheamicin that may be used include, but arenot limited to, γ₁ ^(I), α₂ ^(I), α₃ ^(I), N-acetyl-γ₁ ^(I), PSAG andθ^(I) ₁ (Hinman et al. Cancer Research 53: 3336-3342 (1993) and Lode etal. Cancer Research 58: 2925-2928 (1998)).

Enzymatically active toxins and fragments thereof that can be usedinclude diphtheria A chain, nonbinding active fragments of diphtheriatoxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain,abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordiiproteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII,and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonariaofficinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin,enomycin, and the tricothecenes. See, for example, WO 1993/21232published Oct. 28, 1993.

The present invention further contemplates antibody conjugated with acompound with nucleolytic activity (e.g. a ribonuclease or a DNAendonuclease such as a deoxyribonuclease; DNase).

A variety of radioactive isotopes is available for the production ofradioconjugated antibodies. Examples include At²¹¹, I¹³¹, I¹²⁵, Y⁹⁰,Re¹⁸⁶, Re¹⁸⁸, Sm¹⁵³, Bi²¹², P³² and radioactive isotopes of Lu.

Conjugates of the antibody and cytotoxic agent may be made using avariety of bifunctional protein-coupling agents such asN-succinimidyl-3-(2-pyridyldithiol) propionate (SPDP),succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate,iminothiolane (IT), bifunctional derivatives of imidoesters (such asdimethyl adipimidate HCl), active esters (such as disuccinimidylsuberate), aldehydes (such as glutareldehyde), bis-azido compounds (suchas bis (p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (suchas bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such astolyene 2,6-diisocyanate), and bis-active fluorine compounds (such as1,5-difluoro-2,4-dinitrobenzene). For example, a ricin immunotoxin canbe prepared as described in Vitetta et al. Science 238: 1098 (1987).Carbon-14-labeled 1-isothiocyanatobenzyl-3-methyldiethylenetriaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent forconjugation of radionucleotide to the antibody. See WO 1994/11026. Thelinker may be a “cleavable linker” facilitating release of the cytotoxicdrug in the cell. For example, an acid-labile linker,peptidase-sensitive linker, dimethyl linker, or disulfide-containinglinker (Chari et al. Cancer Research 52: 127-131 (1992)) may be used.

Alternatively, a fusion protein comprising the antibody and cytotoxicagent may be made, e.g. by recombinant techniques or peptide synthesis.

In yet another embodiment, the antibody may be conjugated to a“receptor” (such as streptavidin) for utilization in tumor pretargetingwherein the antibody-receptor conjugate is administered to the subject,followed by removal of unbound conjugate from the circulation using aclearing agent and then administration of a “ligand” (e.g. avidin) thatis conjugated to a cytotoxic agent (e.g. a radionucleotide).

The antibodies of the present invention may also be conjugated with aprodrug-activating enzyme that converts a prodrug (e.g. a peptidylchemotherapeutic agent, see WO 1981/01145) to an active anti-cancerdrug. See, for example, WO 1988/07378 and U.S. Pat. No. 4,975,278.

The enzyme component of such conjugates includes any enzyme capable ofacting on a prodrug in such a way so as to convert it into its moreactive, cytotoxic form.

Enzymes that are useful in the method of this invention include, but arenot limited to, alkaline phosphatase useful for convertingphosphate-containing prodrugs into free drugs; arylsulfatase useful forconverting sulfate-containing prodrugs into free drugs; cytosinedeaminase useful for converting non-toxic 5-fluorocytosine into theanti-cancer drug, 5-fluorouracil; proteases, such as serratia protease,thermolysin, subtilisin, carboxypeptidases, and cathepsins (such ascathepsins B and L), that are useful for converting peptide-containingprodrugs into free drugs; D-alanylcarboxypeptidases, useful forconverting prodrugs that contain D-amino acid substituents;carbohydrate-cleaving enzymes such as β-galactosidase and neuraminidaseuseful for converting glycosylated prodrugs into free drugs; β-lactamaseuseful for converting drugs derivatized with β-lactams into free drugs;and penicillin amidases, such as penicillin V amidase or penicillin Gamidase, useful for converting drugs derivatized at their aminenitrogens with phenoxyacetyl or phenylacetyl groups, respectively, intofree drugs. Alternatively, antibodies with enzymatic activity, alsoknown in the art as “abzymes”, can be used to convert the prodrugs ofthe invention into free active drugs (see, e.g., Massey, Nature 328:457-458 (1987)). Antibody-abzyme conjugates can be prepared as describedherein for delivery of the abzyme to a tumor cell population.

The enzymes of this invention can be covalently bound to the antibody bytechniques well known in the art such as the use of theheterobifunctional crosslinking reagents discussed above. Alternatively,fusion proteins comprising at least the antigen-binding region of anantibody of the invention linked to at least a functionally activeportion of an enzyme of the invention can be constructed usingrecombinant DNA techniques well known in the art (see, e.g., Neubergeret al., Nature, 312: 604-608 (1984)).

Other modifications of the antibody are contemplated herein. Forexample, the antibody may be linked to one of a variety ofnonproteinaceous polymers, e.g., polyethylene glycol (PEG),polypropylene glycol, polyoxyalkylenes, or copolymers of polyethyleneglycol and polypropylene glycol. Antibody fragments, such as Fab′,linked to one or more PEG molecules are an especially preferredembodiment of the invention.

The antibodies disclosed herein may also be formulated as liposomes.Liposomes containing the antibody are prepared by methods known in theart, such as described in Epstein et al., Proc. Natl. Acad. Sci. USA,82:3688 (1985); Hwang et al., Proc. Natl. Acad. Sci. USA, 77:4030(1980); U.S. Pat. Nos. 4,485,045 and 4,544,545; and WO 1997/38731published Oct. 23, 1997. Liposomes with enhanced circulation time aredisclosed in U.S. Pat. No. 5,013,556.

Particularly useful liposomes can be generated by the reverse-phaseevaporation method with a lipid composition comprisingphosphatidylcholine, cholesterol and PEG-derivatizedphosphatidylethanolamine (PEG-PE). Liposomes are extruded throughfilters of defined pore size to yield liposomes with the desireddiameter. Fab′ fragments of an antibody of the present invention can beconjugated to the liposomes as described in Martin et al. J. Biol. Chem.257: 286-288 (1982) via a disulfide-interchange reaction. Achemotherapeutic agent is optionally contained within the liposome. SeeGabizon et al. J. National Cancer Inst. 81(19)1484 (1989).

Amino acid sequence modification(s) of protein or peptide antibodiesdescribed herein are contemplated. For example, it may be desirable toimprove the binding affinity and/or other biological properties of theantibody. Amino acid sequence variants of the antibody are prepared byintroducing appropriate nucleotide changes into the antibody nucleicacid, or by peptide synthesis. Such modifications include, for example,deletions from, and/or insertions into and/or substitutions of, residueswithin the amino acid sequences of the antibody. Any combination ofdeletion, insertion, and substitution is made to arrive at the finalconstruct, provided that the final construct possesses the desiredcharacteristics. The amino acid changes also may alterpost-translational processes of the antibody, such as changing thenumber or position of glycosylation sites.

A useful method for identification of certain residues or regions of theantibody that are preferred locations for mutagenesis is called“alanine-scanning mutagenesis” as described by Cunningham and WellsScience, 244:1081-1085 (1989). Here, a residue or group of targetresidues are identified (e.g., charged residues such as arg, asp, his,lys, and glu) and replaced by a neutral or negatively charged amino acid(most preferably alanine or polyalanine) to affect the interaction ofthe amino acids with antigen. Those amino acid locations demonstratingfunctional sensitivity to the substitutions then are refined byintroducing further or other variants at, or for, the sites ofsubstitution. Thus, while the site for introducing an amino acidsequence variation is predetermined, the nature of the mutation per seneed not be predetermined. For example, to analyze the performance of amutation at a given site, ala scanning or random mutagenesis isconducted at the target codon or region and the expressed antibodyvariants are screened for the desired activity.

Amino acid sequence insertions include amino- and/or carboxyl-terminalfusions ranging in length from one residue to polypeptides containing ahundred or more residues, as well as intrasequence insertions of singleor multiple amino acid residues. Examples of terminal insertions includean antibody with an N-terminal methionyl residue or the antibody fusedto a cytotoxic polypeptide. Other insertional variants of the antibodymolecule include the fusion to the N- or C-terminus of the antibody ofan enzyme, or a polypeptide that increases the serum half-life of theantibody.

Another type of variant is an amino acid substitution variant. Thesevariants have at least one amino acid residue in the antibody moleculereplaced by a different residue. The sites of greatest interest forsubstitutional mutagenesis of antibodies include the hypervariableregions, but FR alterations are also contemplated. Conservativesubstitutions are shown in Table 1 under the heading of “preferredsubstitutions”. If such substitutions result in a change in biologicalactivity, then more substantial changes, denominated “exemplarysubstitutions” in Table 1, or as further described below in reference toamino acid classes, may be introduced and the products screened.

TABLE 1 Original Exemplary Preferred Residue Substitutions SubstitutionsAla (A) Val; Leu; Ile Val Arg (R) Lys; Gln; Asn Lys Asn (N) Gln; His;Asp, Lys; Arg Gln Asp (D) Glu; Asn Glu Cys (C) Ser; Ala Ser Gln (Q) Asn;Glu Asn Glu (E) Asp; Gln Asp Gly (G) Ala Ala His (H) Asn; Gln; Lys; ArgArg Ile (I) Leu; Val; Met; Ala; Leu Phe; Norleucine Leu (L) Norleucine;Ile; Val; Ile Met; Ala; Phe Lys (K) Arg; Gln; Asn Arg Met (M) Leu; Phe;Ile Leu Phe (F) Trp; Leu; Val; Ile; Ala; Tyr Tyr Pro (P) Ala Ala Ser (S)Thr Thr Thr (T) Val; Ser Ser Trp (W) Tyr; Phe Tyr Tyr (Y) Trp; Phe; Thr;Ser Phe Val (V) Ile; Leu; Met; Phe; Leu Ala; Norleucine

Substantial modifications in the biological properties of the antibodyare accomplished by selecting substitutions that differ significantly intheir effect on maintaining (a) the structure of the polypeptidebackbone in the area of the substitution, for example, as a sheet orhelical conformation, (b) the charge or hydrophobicity of the moleculeat the target site, or (c) the bulk of the side chain. Amino acids maybe grouped according to similarities in the properties of their sidechains (in A. L. Lehninger, in Biochemistry, second ed., pp. 73-75,Worth Publishers, New York (1975)):

-   -   (1) non-polar: Ala (A), Val (V), Leu (L), Ile (I), Pro (P), Phe        (F), Trp (W), Met (M)    -   (2) uncharged polar: Gly (G), Ser (S), Thr (T), Cys (C), Tyr        (Y), Asn (N), Gln (O)    -   (3) acidic: Asp (D), Glu (E)    -   (4) basic: Lys (K), Arg (R), H is(H)

Alternatively, naturally occurring residues may be divided into groupsbased on common side-chain properties:

-   -   (1) hydrophobic: Norleucine, Met, Ala, Val, Leu, Ile;    -   (2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gln;    -   (3) acidic: Asp, Glu;    -   (4) basic: His, Lys, Arg;    -   (5) residues that influence chain orientation: Gly, Pro;    -   (6) aromatic: Trp, Tyr, Phe.

Non-conservative substitutions will entail exchanging a member of one ofthese classes for another class.

Any cysteine residue not involved in maintaining the proper conformationof the antibody also may be substituted, generally with serine, toimprove the oxidative stability of the molecule and prevent aberrantcrosslinking Conversely, cysteine bond(s) may be added to the antibodyto improve its stability (particularly where the antibody is an antibodyfragment such as an Fv fragment).

A particularly preferred type of substitutional variant involvessubstituting one or more hypervariable region residues of a parentantibody. Generally, the resulting variant(s) selected for furtherdevelopment will have improved biological properties relative to theparent antibody from which they are generated. A convenient way forgenerating such substitutional variants is affinity maturation usingphage display. Briefly, several hypervariable region sites (e.g. 6-7sites) are mutated to generate all possible amino acid substitutions ateach site. The antibody variants thus generated are displayed in amonovalent fashion from filamentous phage particles as fusions to thegene III product of M13 packaged within each particle. Thephage-displayed variants are then screened for their biological activity(e.g. binding affinity) as herein disclosed. In order to identifycandidate hypervariable region sites for modification, alanine-scanningmutagenesis can be performed to identify hypervariable region residuescontributing significantly to antigen binding. Alternatively, or inadditionally, it may be beneficial to analyze a crystal structure of theantigen-antibody complex to identify contact points between the antibodyand antigen. Such contact residues and neighboring residues arecandidates for substitution according to the techniques elaboratedherein. Once such variants are generated, the panel of variants issubjected to screening as described herein and antibodies with superiorproperties in one or more relevant assays may be selected for furtherdevelopment.

Another type of amino acid variant of the antibody alters the originalglycosylation pattern of the antibody. Such altering includes deletingone or more carbohydrate moieties found in the antibody, and/or addingone or more glycosylation sites that are not present in the antibody.

Glycosylation of polypeptides is typically either N-linked or O-linked.N-linked refers to the attachment of the carbohydrate moiety to the sidechain of an asparagine residue. The tripeptide sequencesasparagine-X-serine and asparagine-X-threonine, where X is any aminoacid except proline, are the recognition sequences for enzymaticattachment of the carbohydrate moiety to the asparagine side chain.Thus, the presence of either of these tripeptide sequences in apolypeptide creates a potential glycosylation site. O-linkedglycosylation refers to the attachment of one of the sugarsN-aceylgalactosamine, galactose, or xylose to a hydroxyamino acid, mostcommonly serine or threonine, although 5-hydroxyproline or5-hydroxylysine may also be used.

Addition of glycosylation sites to the antibody is convenientlyaccomplished by altering the amino acid sequence such that it containsone or more of the above-described tripeptide sequences (for N-linkedglycosylation sites). The alteration may also be made by the additionof, or substitution by, one or more serine or threonine residues to thesequence of the original antibody (for O-linked glycosylation sites).

Where the antibody comprises an Fc region, the carbohydrate attachedthereto may be altered. For example, antibodies with a maturecarbohydrate structure that lacks fucose attached to an Fc region of theantibody are described in US 2003/0157108 (Presta, L.). See also US2004/0093621 (Kyowa Hakko Kogyo Co., Ltd.). Antibodies with a bisectingN-acetylglucosamine (G1cNAc) in the carbohydrate attached to an Fcregion of the antibody are referenced in WO 2003/011878, Jean-Mairet etal. and U.S. Pat. No. 6,602,684, Umana et al. Antibodies with at leastone galactose residue in the oligosaccharide attached to an Fc region ofthe antibody are reported in WO 1997/30087, Patel et al. See, also, WO1998/58964 (Raju, S.) and WO 1999/22764 (Raju, S.) concerning antibodieswith altered carbohydrate attached to the Fc region thereof.

The preferred glycosylation variant herein comprises an Fc region,wherein a carbohydrate structure attached to the Fc region lacks fucose.Such variants have improved ADCC function. Optionally, the Fc regionfurther comprises one or more amino acid substitutions therein thatfurther improve ADCC, for example, substitutions at positions 298, 333,and/or 334 of the Fc region (Eu numbering of residues). Examples ofpublications related to “defucosylated” or “fucose-deficient” antibodiesinclude: US 2003/0157108; WO 2000/61739; WO 2001/29246; US 2003/0115614;US 2002/0164328; US 2004/0093621; US 2004/0132140; US 2004/0110704; US2004/0110282; US 2004/0109865; WO 2003/085119; WO 2003/084570; WO2005/035586; WO 2005/035778; Okazaki et al. J. Mol. Biol. 336:1239-1249(2004); and Yamane-Ohnuki et al. Biotech. Bioeng.87: 614 (2004).Examples of cell lines producing defucosylated antibodies include Lec13CHO cells deficient in protein fucosylation (Ripka et al. Arch. Biochem.Biophys. 249:533-545 (1986); US 2003/0157108, Presta, L; and WO2004/056312, Adams et al., especially at Example 11), and knockout celllines, such as alpha-1,6-fucosyltransferase gene, FUT8,-knockout CHOcells (Yamane-Ohnuki et al. Biotech. Bioeng. 87: 614 (2004)).

Nucleic acid molecules encoding amino acid sequence variants of theantibody are prepared by a variety of methods known in the art. Thesemethods include, but are not limited to, isolation from a natural source(in the case of naturally occurring amino acid sequence variants) orpreparation by oligonucleotide-mediated (or site-directed) mutagenesis,PCR mutagenesis, and cassette mutagenesis of an earlier prepared variantor a non-variant version of the antibody.

It may be desirable to modify the antibody of the invention with respectto effector function, e.g. so as to enhance ADCC and/or CDC of theantibody. This may be achieved by introducing one or more amino acidsubstitutions in an Fc region of an antibody. Alternatively oradditionally, cysteine residue(s) may be introduced in the Fc region,thereby allowing interchain disulfide bond formation in this region. Thehomodimeric antibody thus generated may have improved internalizationcapability and/or increased complement-mediated cell killing and ADCC.See Caron et al., J. Exp Med. 176:1191-1195 (1992) and Shopes, B. J.Immunol. 148:2918-2922 (1992). Homodimeric antibodies with enhancedanti-tumor activity may also be prepared using heterobifunctionalcross-linkers as described in Wolff et al. Cancer Research 53:2560-2565(1993). Alternatively, an antibody can be engineered that has dual Fcregions and may thereby have enhanced complement lysis and ADCCcapabilities. See Stevenson et al. Anti-Cancer Drug Design 3:219-230(1989).

WO 2000/42072 (Presta, L.) describes antibodies with improved ADCCfunction in the presence of human effector cells, where the antibodiescomprise amino acid substitutions in the Fc region thereof. Preferably,the antibody with improved ADCC comprises substitutions at positions298, 333, and/or 334 of the Fc region. Preferably, the altered Fc regionis a human IgGl Fc region comprising or consisting of substitutions atone, two, or three of these positions.

Antibodies with altered Clq binding and/or CDC are described in WO1999/51642 and U.S. Pat. Nos. 6,194,551, 6,242,195, 6,528,624, and6,538,124 (Idusogie et al.). The antibodies comprise an amino acidsubstitution at one or more of amino acid positions 270, 322, 326, 327,329, 313, 333, and/or 334 of the Fc region thereof.

To increase the serum half-life of the antibody, one may incorporate asalvage receptor binding epitope into the antibody (especially anantibody fragment) as described in U.S. Pat. No. 5,739,277, for example.As used herein, the term “salvage receptor binding epitope” refers to anepitope of the Fc region of an IgG molecule (e.g., IgG₁, IgG₂, IgG₃, orIgG₄) that is responsible for increasing the in vivo serum half-life ofthe IgG molecule. Antibodies with substitutions in an Fc region thereofand increased serum half-lives are also described in WO 2000/42072(Presta, L.).

Engineered antibodies with three or more (preferably four) functionalantigen-binding sites are also contemplated (US 2002/0004587 A1, Milleret al.).

VII. Pharmaceutical Formulations

Therapeutic formulations of the antibodies used in accordance with thepresent invention are prepared for storage by mixing an antibody havingthe desired degree of purity with optional pharmaceutically acceptablecarriers, excipients, or stabilizers (Remington's PharmaceuticalSciences 16th edition, Osol, A. Ed. (1980)), in the form of lyophilizedformulations or aqueous solutions. Acceptable carriers, excipients, orstabilizers are nontoxic to recipients at the dosages and concentrationsemployed, and include buffers such as phosphate, histidine, citrate, andother organic acids; salts such as sodium chloride, calcium chloride andammonium sulfate; antioxidants including ascorbic acid and methionine;preservatives (such as octadecyldimethylbenzyl ammonium chloride;hexamethonium chloride; benzalkonium chloride, benzethonium chloride;phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol);low-molecular-weight (less than about 10 residues) polypeptides;proteins, such as serum albumin, gelatin, or immunoglobulins;hydrophilic polymers such as polyvinylpyrrolidone; amino acids such asglycine, glutamine, asparagine, histidine, arginine, or lysine;monosaccharides, disaccharides, and other carbohydrates includingglucose, mannose, or dextrins; chelating agents such as EDTA; sugarssuch as sucrose, mannitol, trehalose or sorbitol; salt-formingcounter-ions such as sodium; metal complexes (e.g. Zn-proteincomplexes); and/or non-ionic surfactants such as TWEEN™, PLURONICS™, orPEG.

Exemplary anti-factor D antibody, or antigen-binding fragment thereofformulations are described in U.S. Pat. Nos. 8,067,002, 8,193,329,8,187,604, 8,372,403, 8,273,352, 6,954,107, 7,943,135, 7,439,331,7,112,327, 8,124,090, and 8,236,317.

Lyophilized formulations adapted for subcutaneous administration aredescribed, for example, in U.S. Pat. No. 6,267,958 (Andya et al.).Lyophilized formulations adapted for intravitreal administration aredescribed, for example, in U.S. Pat. Nos. 7,807,164, 8,481,046. Suchlyophilized formulations may be reconstituted with a suitable diluent toa high protein concentration (described for example, in U.S. Pat. No.8,142,776) and the reconstituted formulation may be administeredsubcutaneously or intravitreally to the mammal to be treated herein.

Crystallized forms of the antibody are also contemplated. See, forexample, US 2002/0136719A1 (Shenoy et al.).

The formulation herein may also contain more than one active compound (asecond medicament) as necessary for the particular indication beingtreated, preferably those with complementary activities that do notadversely affect each other. For example, it may be desirable to furtherprovide a VEGF inhibitor in the formulation. The type and effectiveamounts of such other agents (called herein second medicaments, whereinthe first medicament is the anti-factor D antibody) depend, for example,on the amount of antibody present in the formulation, the type ofdegenerative disease being treated, and clinical parameters of thesubjects.

The active ingredients may also be entrapped in microcapsules prepared,for example, by coacervation techniques or by interfacialpolymerization, for example, hydroxymethylcellulose orgelatin-microcapsules and poly-(methylmethacylate) microcapsules,respectively, in colloidal drug-delivery systems (for example,liposomes, albumin microspheres, microemulsions, nano-particles andnanocapsules) or in macroemulsions. Such techniques are disclosed, e.g.,in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed.(1980).

Sustained-release preparations may be prepared. Suitable examples ofsustained-release preparations include semipermeable matrices of solidhydrophobic polymers containing the antibody, which matrices are in theform of shaped articles, e.g. films, or microcapsules. Examples ofsustained-release matrices include polyesters, hydrogels (for example,poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides(U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and γethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradablelactic acid-glycolic acid copolymers such as the LUPRON DEPOT™(injectable microspheres composed of lactic acid-glycolic acid copolymerand leuprolide acetate), and poly-D-(−)-3-hydroxybutyric acid.

The formulations to be used for in vivo administration must be sterile.This is readily accomplished by filtration through sterile filtrationmembranes.

VIII. Articles of Manufacture

Various articles of manufacture are contemplated within the scope of theinvention. In another embodiment of the invention, an article ofmanufacture containing materials useful for the treatment ofdegenerative disease described above is provided. Preferably, thearticle of manufacture comprises (a) a container comprising acomposition comprising an anti-factor D antibody or antigen-bindingfragment thereof and a pharmaceutically acceptable carrier or diluentwithin the container; and (b) a package insert with instructions fortreating degenerative disease in a subject, wherein the instructionsindicate that an amount of the antibody is administered to the subjectthat is effective to provide an initial antibody exposure of about 0.5to 4 grams followed by a second antibody exposure of about 0.5 to 4grams, wherein the second exposure is not provided until from about 16to 54 weeks from the initial exposure and each of the antibody exposuresis provided to the subject as a single dose or as two or three separatedoses of antibody.

The package insert is on or associated with the container. Suitablecontainers include, for example, bottles, vials, syringes, etc. Thecontainers may be formed from a variety of materials such as glass orplastic. The container holds or contains a composition that is effectivefor treating AMD and may have a sterile access port (for example, thecontainer may be an intravenous solution bag or a vial having a stopperpierceable by a hypodermic injection needle). At least one active agentin the composition is the antibody. The label or package insertindicates that the composition is used for treating degenerative diseasein a subject eligible for treatment with specific guidance regardingdosing amounts and intervals of antibody and any other drug beingprovided. The article of manufacture may further comprise a secondcontainer comprising a pharmaceutically acceptable diluent buffer, suchas bacteriostatic water for injection (BWFI), phosphate-buffered saline,Ringer's solution, and dextrose solution. The article of manufacture maystill further comprise a second or third container comprising a secondmedicament, wherein the anti-factor D antibody or antigen-bindingfragment thereof is a first medicament, where the article furthercomprises instructions on the package insert for treating the subjectwith the second medicament. Exemplary second medicaments include achemotherapeutic agent, an immunosuppressive agent, an anti-malarialagent, a cytotoxic agent, an integrin antagonist, a cytokine antagonist,or a hormone. In some embodiments, the second medicament is achemotherapeutic agent, an anti-malarial agent, or an immunosuppressiveagent, including, e.g., hydroxychloroquine, chloroquine, quinacrine,cyclophosphamide, prednisone, mycophenolate mofetil, methotrexate,azathiprine, or 6-mercaptopurine; a corticosteroid such as prednisone(along with optionally methotrexate, hydroxychloroquine, chloroquine,quinacrine, MMF, or azathioprine with or without 6-mercaptopurine); or acorticosteroid such as prednisone as well as MMF or cyclophosphamide.The article of manufacture may further include other materials desirablefrom a commercial and user standpoint, including other buffers,diluents, filters, needles, and syringes.

In another aspect, the invention provides an article of manufacturecomprising an IVT or long-acting delivery device, which delivers to apatient a fixed dose of an anti-factor D antibody or antigen-bindingfragment thereof, wherein the fixed dose is in the microgram tomilligram range of the anti-factor D antibody or antigen-bindingfragment thereof. In some embodiments, the fixed dose is about 10 mgmonthly or about 10 mg every other month. In some embodiments, theconcentration of the antibody in the device is about 10 mg. In anotheraspect, the invention provides an article of manufacture comprising ananti-factor D antibody or antigen-binding fragment thereof in aconcentration of about 10 mg. In some embodiments, the anti-factor Dantibody comprises a light chain comprising HVR-L1 comprising the aminoacid sequence ITSTDIDDDMN (SEQ ID NO:1), HVR-L2 comprising the aminoacid sequence GGNTLRP (SEQ ID NO:2), and HVR-L3 comprising the aminoacid sequence LQSDSLPYT (SEQ ID NO: 3); and/or a heavy chain comprisingHVR-H1 comprising the amino acid sequence GYTFTNYGMN (SEQ ID NO: 4),HVR-H2 comprising the amino acid sequence WINTYTGETTYADDFKG (SEQ IDNO:5), and HVR-H3 comprising the amino acid sequence EGGVNN (SEQ IDNO:6) In some embodiments, the antibody comprises a heavy chain variableregion sequence of at least 95% sequence identity to the amino acidsequence of SEQ ID NO:7; and/or a light chain variable region sequenceof at least 95% sequence identity to the amino acid sequence of SEQ IDNO:8. In some embodiments, the antibody comprises a heavy chain variableregion comprising the amino acid sequence of SEQ ID NO:7; and/or a lightchain variable region comprising the amino acid sequence of SEQ ID NO:8.In some embodiments, the antibody is lampalizumab having CASregistration number 1278466-20-8. In some embodiments, the anti-factor Dantibody may be a monoclonal antibody, antibody fragment, chimericantibody, humanized antibody, single-chain antibody or antibody thatcompetitively inhibits the binding of an anti-factor D antibody to itsrespective antigenic epitope. In one embodiment, the anti-factor Dantibody competitively inhibits the binding of the anti-factor Dantibody comprising a light chain comprising HVR-L1 comprising the aminoacid sequence ITSTDIDDDMN (SEQ ID NO:1), HVR-L2 comprising the aminoacid sequence GGNTLRP (SEQ ID NO:2), and HVR-L3 comprising the aminoacid sequence LQSDSLPYT (SEQ ID NO: 3); and/or a heavy chain comprisingHVR-H1 comprising the amino acid sequence GYTFTNYGMN (SEQ ID NO: 4),HVR-H2 comprising the amino acid sequence WINTYTGETTYADDFKG (SEQ IDNO:5), and HVR-H3 comprising the amino acid sequence EGGVNN (SEQ IDNO:6) to its respective antigenic epitope. In one embodiment, theanti-factor D antibody competitively inhibits the binding of theantibody comprising a heavy chain variable region sequence of at least95% sequence identity to the amino acid sequence of SEQ ID NO:7; and/ora light chain variable region sequence of at least 95% sequence identityto the amino acid sequence of SEQ ID NO:8 to its respective antigenicepitope. In one embodiment, the anti-factor D antibody competitivelyinhibits the binding of the antibody comprising a heavy chain sequenceof at least 95% sequence identity to the amino acid sequence of SEQ IDNO:15; and/or a light chain sequence of at least 95% sequence identityto the amino acid sequence of SEQ ID NO:16 to its respective antigenicepitope. In one embodiment, the anti-factor D antibody competitivelyinhibits the binding of the antibody comprising a heavy chain variableregion comprising the amino acid sequence of SEQ ID NO:7; and/or a lightchain variable region comprising the amino acid sequence of SEQ ID NO:8to its respective antigenic epitope. In one embodiment, the anti-factorD antibody competitively inhibits the binding of the antibody comprisinga heavy chain comprising the amino acid sequence of SEQ ID NO:15; and/ora light chain comprising the amino acid sequence of SEQ ID NO:16 to itsrespective antigenic epitope. In one embodiment, the anti-factor Dantibody competitively inhibits the binding of lampalizumab having CASregistration number 1278466-20-8 to its respective antigenic epitope. Insome embodiments, the anti-factor D antibody binds to the same epitopeon factor D bound by another factor D antibody. In one embodiment, theanti-factor D antibody binds to the same epitope on factor D bound bythe anti-factor D antibody comprising a light chain comprising HVR-L1comprising the amino acid sequence ITSTDIDDDMN (SEQ ID NO:1), HVR-L2comprising the amino acid sequence GGNTLRP (SEQ ID NO:2), and HVR-L3comprising the amino acid sequence LQSDSLPYT (SEQ ID NO: 3); and/or aheavy chain comprising HVR-H1 comprising the amino acid sequenceGYTFTNYGMN (SEQ ID NO: 4), HVR-H2 comprising the amino acid sequenceWINTYTGETTYADDFKG (SEQ ID NO:5), and HVR-H3 comprising the amino acidsequence EGGVNN (SEQ ID NO:6). In one embodiment, the anti-factor Dantibody binds to the same epitope on factor D bound by the antibodycomprising a heavy chain variable region sequence of at least 95%sequence identity to the amino acid sequence of SEQ ID NO:7; and/or alight chain variable region sequence of at least 95% sequence identityto the amino acid sequence of SEQ ID NO:8. In one embodiment, theanti-factor D antibody binds to the same epitope on factor D bound bythe antibody comprising a heavy chain sequence of at least 95% sequenceidentity to the amino acid sequence of SEQ ID NO:15; and/or a lightchain sequence of at least 95% sequence identity to the amino acidsequence of SEQ ID NO:16. In one embodiment, the anti-factor D antibodybinds to the same epitope on factor D bound by the antibody comprising aheavy chain variable region comprising the amino acid sequence of SEQ IDNO:7; and/or a light chain variable region comprising the amino acidsequence of SEQ ID NO:8. In one embodiment, the anti-factor D antibodybinds to the same epitope on factor D bound by the antibody comprising aheavy chain comprising the amino acid sequence of SEQ ID NO:15; and/or alight chain comprising the amino acid sequence of SEQ ID NO:16. In oneembodiment, the anti-factor D antibody binds to the same epitope onfactor D bound by lampalizumab having CAS registration number1278466-20-8.

IX. Exemplar Embodiments

The invention includes a method of treating a patient having adegenerative disease, the method comprising:

-   -   (a) determining the presence of at least one degenerative        disease-associated polymorphism in a sample from the patient;        -   (i) by providing a nucleic acid sample the patient;        -   (ii) genotyping the presence of at least one degenerative            disease-associated polymorphism wherein the polymorphism is            a risk allele selected from the group consisting of a CFI            allele, a CFH allele, a C2 allele, a CFB allele, or a C3            allele;    -   (b) identifying the patient as more likely to respond to a        therapy comprising anti-factor D antibody, or an antigen-binding        fragment thereof, when at least one risk allele, selected from        the group consisting of a CFI allele, a CFH allele, a C2 allele,        a CFB allele, or a C3 allele is present; and    -   (c) administering the anti-factor D antibody, or antigen-binding        fragment thereof, to the patient when at least one risk allele        selected from the group consisting of a CFI allele, a CFH        allele, a C2 allele, a C3B allele, or a C3 allele is present. In        one embodiment, the CFI allele is an equivalent allele thereof,        the CFH allele is an equivalent allele thereof, the C2 allele is        an equivalent allele thereof, the CFB allele is an equivalent        allele thereof, or the C3 allele is an equivalent allele        thereof. In a further embodiment, the CFI allele comprises a G        at the single nucleotide polymorphism (SNP) rs4698775 or        rs17440077, the CFH allele comprises an A at the single        nucleotide polymorphism (SNP) rs10737680 or a G at the single        nucleotide polymorphism (SNP) rs1329428, the C2 allele comprises        a G at the single nucleotide polymorphism (SNP) rs429608, the        CFB allele comprises a G at the single nucleotide polymorphism        (SNP) rs429608, and the C3 allele comprises a G at the single        nucleotide polymorphism (SNP) rs2230199. In an even further        embodiment, the sample is a blood sample, saliva, cheek swab,        tissue sample or a sample of a bodily fluid. In an even further        embodiment, the nucleic acid sample comprises DNA. In another        embodiment, the nucleic acid sample comprises RNA. In another        embodiment, the nucleic acid sample is amplified. In another        embodiment, the nucleic acid sample is amplified by a polymerase        chain reaction. In another embodiment, at least one polymorphism        is detected by polymerase chain reaction. In another embodiment,        at least one polymorphism is detected by sequencing. In another        embodiment, at least one polymorphism is detected by a technique        selected from the group consisting of scanning probe and        nanopore DNA sequencing, pyrosequencing, Denaturing Gradient Gel        Electrophoresis (DGGE), Temporal Temperature Gradient        Electrophoresis (TTGE), Zn(II)-cyclen polyacrylamide gel        electrophoresis, homogeneous fluorescent PCR-based single        nucleotide polymorphism analysis, phosphate-affinity        polyacrylamide gel electrophoresis, high-throughput SNP        genotyping platforms, molecular beacons, 5′nuclease reaction,        Taqman assay, MassArray (single base primer extension coupled        with matrix-assisted laser desorption/ionization time-of-flight        mass spectrometry), trityl mass tags, genotyping platforms (such        as the Invader Assay®), single base primer extension (SBE)        assays, PCR amplification (e.g. PCR amplification on magnetic        nanoparticles (MNPs), restriction enzyme analysis of PCR        products (RFLP methods), allele-specific PCR, multiple primer        extension (MPEX), and isothermal smart amplification. In another        embodiment, at least one polymorphism is detected by        amplification of a target region containing at least one        polymorphism, and hybridization with at least one        sequence-specific oligonucleotide that hybridizes under        stringent conditions to at least one polymorphism and detecting        the hybridization. In another embodiment, the presence of one or        two alleles of the G genotype at the SNP rs4698775, SNP        rs17440077, SNP rs1329428, SNP rs429608 or SNP rs2230199 or one        or two alleles of the A genotype at the SNP rs10737680 in the        patient indicates an increased likelihood of response to        anti-factor D antibody treatment. In another embodiment, a        polymorphism that is in linkage disequilibrium with at least one        single nucleotide polymorphism selected from the group        consisting of single nucleotide polymorphism (SNP) rs4698775,        rs17440077, rs10737680, rs1329428, rs429608, and rs2230199 is        detected. In another embodiment, the degenerative disease is age        related macular degeneration. In another embodiment, the age        related macular degeneration is early, intermediate or advanced        AMD. In another embodiment, the advanced AMD is geographic        atrophy. In another embodiment, the anti-factor D antibody, or        antigen-binding fragment thereof is lampalizumab.

The invention further includes a method of identifying a patient havinga degenerative disease as more likely to respond to a therapy comprisingan anti-factor D antibody, or antigen-binding fragment thereof, themethod comprising:

-   -   (a) determining the presence of at least one degenerative        disease-associated polymorphism in a sample from the patient;        -   (i) by providing a nucleic acid sample from the patient;        -   (ii) genotyping the presence of at least one degenerative            disease-associated polymorphism wherein the polymorphism is            a risk allele selected from the group consisting of a CFI            allele, a CFH allele, a C2 allele, a CFB allele, or a C3            allele;    -   (b) identifying the patient as more likely to respond to a        therapy comprising anti-factor D antibody, or an antigen-binding        fragment thereof, when at least one risk allele, selected from        the group consisting of a CFI allele, a CFH allele, a C2 allele,        a CFB allele, or a C3 allele is present; and    -   (c) selecting the therapy comprising anti-factor D antibody, or        antigen binding fragment thereof. In one embodiment, the CFI        allele is an equivalent allele thereof, the CFH allele is an        equivalent allele thereof, the C2 allele is an equivalent allele        thereof, the CFB allele is an equivalent allele thereof, or the        C3 allele is an equivalent allele thereof In another embodiment,        the CFI allele comprises a G at the single nucleotide        polymorphism (SNP) rs4698775 or rs17440077, the CFH allele        comprises an A at the single nucleotide polymorphism (SNP)        rs10737680 or a G at the single nucleotide polymorphism (SNP)        rs1329428, the C2 allele comprises a G at the single nucleotide        polymorphism (SNP) rs429608, the CFB allele comprises a G at the        single nucleotide polymorphism (SNP) rs429608, and the C3 allele        comprises a G at the single nucleotide polymorphism (SNP)        rs2230199. In another embodiment, the sample is a blood sample,        saliva, cheek swab, tissue sample or a sample of a bodily fluid.        In another embodiment, the nucleic acid sample comprises DNA. In        another embodiment, the nucleic acid sample comprises RNA. In        another embodiment, the nucleic acid sample is amplified. In        another embodiment, the nucleic acid sample is amplified by a        polymerase chain reaction. In another embodiment, at least one        polymorphism is detected by polymerase chain reaction. In        another embodiment, at least one polymorphism is detected by        sequencing. In another embodiment, at least one polymorphism is        detected by a technique selected from the group consisting of        scanning probe and nanopore DNA sequencing, pyrosequencing,        Denaturing Gradient Gel Electrophoresis (DGGE), Temporal        Temperature Gradient Electrophoresis (TTGE), Zn(II)-cyclen        polyacrylamide gel electrophoresis, homogeneous fluorescent        PCR-based single nucleotide polymorphism analysis,        phosphate-affinity polyacrylamide gel electrophoresis,        high-throughput SNP genotyping platforms, molecular beacons,        5′nuclease reaction, Taqman assay, MassArray (single base primer        extension coupled with matrix-assisted laser        desorption/ionization time-of-flight mass spectrometry), trityl        mass tags, genotyping platforms (such as the Invader Assay®),        single base primer extension (SBE) assays, PCR amplification        (e.g. PCR amplification on magnetic nanoparticles (MNPs),        restriction enzyme analysis of PCR products (RFLP methods),        allele-specific PCR, multiple primer extension (MPEX), and        isothermal smart amplification. In another embodiment, at least        one polymorphism is detected by amplification of a target region        containing at least one polymorphism, and hybridization with at        least one sequence-specific oligonucleotide that hybridizes        under stringent conditions to at least one polymorphism and        detecting the hybridization. In another embodiment, the presence        of one or two alleles of the G genotype at the SNP rs4698775,        SNP rs17440077, SNP rs1329428, SNP rs429608 or SNP rs2230199 or        one or two alleles of the A genotype at the SNP rs10737680 in        the patient indicates an increased likelihood of response to        anti-factor D antibody treatment. In another embodiment, a        polymorphism that is in linkage disequilibrium with at least one        single nucleotide polymorphism selected from the group        consisting of single nucleotide polymorphism (SNP) rs4698775,        rs17440077, rs10737680, rs1329428, rs429608, and rs2230199 is        detected. In another embodiment, the degenerative disease is age        related macular degeneration. In another embodiment, the age        related macular degeneration is early, intermediate or advanced        AMD. In another embodiment, the advanced AMD is geographic        atrophy. In another embodiment, the anti-factor D antibody, or        fragment thereof is lampalizumab. In another embodiment,

The invention further includes a method of optimizing therapeuticefficacy of treatment of a patient having a degenerative disease with ananti-factor D antibody, or antigen binding fragment thereof, the methodcomprising:

-   -   (a) determining the presence of at least one degenerative        disease-associated polymorphism n a sample from the patient;        -   (i) by providing a nucleic acid sample from the patient;        -   (ii) genotyping the presence of at least one degenerative            disease-associated polymorphism wherein the polymorphism is            a risk allele, selected from the group consisting of a CFI            allele, a CFH allele, a C2 allele, a CFB allele, or a C3            allele;    -   (b) identifying the patient as more likely to respond to a        therapy comprising anti-factor D antibody, or an antigen-binding        fragment thereof, when at least one risk allele, selected from        the group consisting of a CFI allele, a CFH allele, a C2 allele,        a CFB allele, or a C3 allele is present; and    -   (c) selecting the therapy comprising anti-factor D antibody, or        antigen-binding fragment thereof. In another embodiment, the CFI        allele is an equivalent allele thereof, the CFH allele is an        equivalent allele thereof, the C2 allele is an equivalent allele        thereof, the CFB allele is an equivalent allele thereof, or the        C3 allele is an equivalent allele thereof In another embodiment,        the CFI allele comprises a G at the single nucleotide        polymorphism (SNP) rs4698775 or rs17440077, the CFH allele        comprises an A at the single nucleotide polymorphism (SNP)        rs10737680 or a G at the single nucleotide polymorphism (SNP)        rs1329428, the C2 allele comprises a G at the single nucleotide        polymorphism (SNP) rs429608, the CFB allele comprises a G at the        single nucleotide polymorphism (SNP) rs429608, and the C3 allele        comprises a G at the single nucleotide polymorphism (SNP)        rs2230199. In another embodiment, the sample is a blood sample,        saliva, cheek swab, tissue sample or a sample of a bodily fluid.        In another embodiment, the nucleic acid sample comprises DNA. In        another embodiment, the nucleic acid sample comprises RNA. In        another embodiment, the nucleic acid sample is amplified. In        another embodiment, the nucleic acid sample is amplified by a        polymerase chain reaction. In another embodiment, at least one        polymorphism is detected by polymerase chain reaction. In        another embodiment, at least one polymorphism is detected by        sequencing. In another embodiment, at least one polymorphism is        detected by a technique selected from the group consisting of        scanning probe and nanopore DNA sequencing, pyrosequencing,        Denaturing Gradient Gel Electrophoresis (DGGE), Temporal        Temperature Gradient Electrophoresis (TTGE), Zn(II)-cyclen        polyacrylamide gel electrophoresis, homogeneous fluorescent        PCR-based single nucleotide polymorphism analysis,        phosphate-affinity polyacrylamide gel electrophoresis,        high-throughput SNP genotyping platforms, molecular beacons,        5′nuclease reaction, Taqman assay, MassArray (single base primer        extension coupled with matrix-assisted laser        desorption/ionization time-of-flight mass spectrometry), trityl        mass tags, genotyping platforms (such as the Invader Assay®),        single base primer extension (SBE) assays, PCR amplification        (e.g. PCR amplification on magnetic nanoparticles (MNPs),        restriction enzyme analysis of PCR products (RFLP methods),        allele-specific PCR, multiple primer extension (MPEX), and        isothermal smart amplification. In another embodiment, at least        one polymorphism is detected by amplification of a target region        containing at least one polymorphism, and hybridization with at        least one sequence-specific oligonucleotide that hybridizes        under stringent conditions to at least one polymorphism and        detecting the hybridization. In another embodiment, the presence        of one or two alleles of the G genotype at the SNP rs4698775,        SNP rs17440077, SNP rs1329428, SNP rs429608 or SNP rs2230199 or        one or two alleles of the A genotype at the SNP rs10737680 in        the patient indicates an increased likelihood of response to        anti-factor D antibody treatment. In another embodiment, a        polymorphism that is in linkage disequilibrium with at least one        single nucleotide polymorphism selected from the group        consisting of single nucleotide polymorphism (SNP) rs4698775,        rs17440077, rs10737680, rs1329428, rs429608, and rs2230199 is        detected. In another embodiment, the degenerative disease is age        related macular degeneration. In another embodiment, the age        related macular degeneration is early, intermediate or advanced        AMD. In another embodiment, the advanced AMD is geographic        atrophy. In another embodiment, the anti-factor D antibody, or        antigen-binding fragment thereof is lampalizumab.

The invention further includes a method of predicting responsiveness ofa degenerative disease patient to treatment with an anti-factor Dantibody, or antigen-binding fragment thereof, the method comprising

-   -   (a) determining the presence of at least one degenerative        disease-associated polymorphism in a sample from the patient;        -   (i) by providing a nucleic acid sample from the patient;        -   (ii) genotyping the presence of at least one degenerative            disease-associated polymorphism wherein the polymorphism is            a risk allele, selected from the group consisting of a CFI            allele, a CFH allele, a C2 allele, a CFB allele, or a C3            allele;    -   (b) identifying the patient as more likely to respond to a        therapy comprising anti-factor D antibody, or an antigen-binding        fragment thereof, when at least one risk allele, selected from        the group consisting of a CFI allele, a CFH allele, a C2 allele,        a CFB allele, or a C3 allele is present. In one embodiment, the        CFI allele is an equivalent allele thereof, the CFH allele is an        equivalent allele thereof, the C2 allele is an equivalent allele        thereof, the CFB allele is an equivalent allele thereof, or the        C3 allele is an equivalent allele thereof In one embodiment, the        CFI allele comprises a G at the single nucleotide polymorphism        (SNP) rs4698775 or rs17440077, the CFH allele comprises an A at        the single nucleotide polymorphism (SNP) rs10737680 or a G at        the single nucleotide polymorphism (SNP) rs1329428, the C2        allele comprises a G at the single nucleotide polymorphism (SNP)        rs429608, the CFB allele comprises a G at the single nucleotide        polymorphism (SNP) rs429608, and the C3 allele comprises a G at        the single nucleotide polymorphism (SNP) rs2230199. In one        embodiment, the sample is a blood sample, saliva, cheek swab,        tissue sample or a sample of a bodily fluid. In one embodiment,        the nucleic acid sample comprises DNA. In one embodiment, the        nucleic acid sample comprises RNA. In one embodiment, the        nucleic acid sample is amplified. In another embodiment, the        nucleic acid sample is amplified by a polymerase chain reaction.        In another embodiment, at least one polymorphism is detected by        polymerase chain reaction. In another embodiment, at least one        polymorphism is detected by sequencing. In another embodiment,        at least one polymorphism is detected by a technique selected        from the group consisting of scanning probe and nanopore DNA        sequencing, pyrosequencing, Denaturing Gradient Gel        Electrophoresis (DGGE), Temporal Temperature Gradient        Electrophoresis (TTGE), Zn(II)-cyclen polyacrylamide gel        electrophoresis, homogeneous fluorescent PCR-based single        nucleotide polymorphism analysis, phosphate-affinity        polyacrylamide gel electrophoresis, high-throughput SNP        genotyping platforms, molecular beacons, 5′nuclease reaction,        Taqman assay, MassArray (single base primer extension coupled        with matrix-assisted laser desorption/ionization time-of-flight        mass spectrometry), trityl mass tags, genotyping platforms (such        as the Invader Assay®), single base primer extension (SBE)        assays, PCR amplification (e.g. PCR amplification on magnetic        nanoparticles (MNPs), restriction enzyme analysis of PCR        products (RFLP methods), allele-specific PCR, multiple primer        extension (MPEX), and isothermal smart amplification. In another        embodiment, at least one polymorphism is detected by        amplification of a target region containing at least one        polymorphism, and hybridization with at least one        sequence-specific oligonucleotide that hybridizes under        stringent conditions to at least one polymorphism and detecting        the hybridization. In another embodiment, the presence of one or        two alleles of the G genotype at the SNP rs4698775, SNP        rs17440077, SNP rs1329428, SNP rs429608 or SNP rs2230199 or one        or two alleles of the A genotype at the SNP rs10737680 in the        patient indicates an increased likelihood of response to        anti-factor D antibody treatment. In another embodiment, a        polymorphism that is in linkage disequilibrium with at least one        single nucleotide polymorphism selected from the group        consisting of single nucleotide polymorphism (SNP) rs4698775,        rs17440077, rs10737680, rs1329428, rs429608, and rs2230199 is        detected. In another embodiment, the degenerative disease is age        related macular degeneration. In another embodiment, the age        related macular degeneration is early, intermediate or advanced        AMD. In another embodiment, the advanced AMD is geographic        atrophy. In another embodiment, the anti-factor D antibody, or        antigen-binding fragment thereof is lampalizumab.

The invention further includes a method of determining the likelihoodthat a degenerative disease patient benefits from treatment with ananti-factor D antibody, or antigen-binding fragment thereof, the methodcomprising

-   -   (a) determining the presence of at least one degenerative        disease-associated polymorphism a sample from the patient;        -   (i) by providing a nucleic acid sample from the patient;        -   (ii) genotyping the presence of at least one degenerative            disease-associated polymorphism wherein the polymorphism is            a risk allele, selected from the group consisting of a CFI            allele, a CFH allele, a C2 allele, a CFB allele, or a C3            allele;    -   (b) identifying the patient as more likely to respond to a        therapy comprising anti-factor D antibody, or an antigen-binding        fragment thereof, when at least one risk allele, selected from        the group consisting of a CFI allele, a CFH allele, a C2 allele,        a CFB allele, or a C3 allele is present. In one embodiment, the        CFI allele is an equivalent allele thereof, the CFH allele is an        equivalent allele thereof, the C2 allele is an equivalent allele        thereof, the CFB allele is an equivalent allele thereof, or the        C3 allele is an equivalent allele thereof. In another        embodiment, the CFI allele comprises a G at the single        nucleotide polymorphism (SNP) rs4698775 or rs17440077, the CFH        allele comprises an A at the single nucleotide polymorphism        (SNP) rs10737680 or a G at the single nucleotide polymorphism        (SNP) rs1329428, the C2 allele comprises a G at the single        nucleotide polymorphism (SNP) rs429608, the CFB allele comprises        a G at the single nucleotide polymorphism (SNP) rs429608, and        the C3 allele comprises a G at the single nucleotide        polymorphism (SNP) rs2230199. In another embodiment, the sample        is a blood sample, saliva, cheek swab, tissue sample or a sample        of a bodily fluid. In another embodiment, the nucleic acid        sample comprises DNA. In another embodiment, the nucleic acid        sample comprises RNA. In another embodiment, the nucleic acid        sample is amplified. In another embodiment, the nucleic acid        sample is amplified by a polymerase chain reaction. In another        embodiment, at least one polymorphism is detected by polymerase        chain reaction. In another embodiment, at least one polymorphism        is detected by sequencing. In another embodiment, at least one        polymorphism is detected by a technique selected from the group        consisting of scanning probe and nanopore DNA sequencing,        pyrosequencing, Denaturing Gradient Gel Electrophoresis (DGGE),        Temporal Temperature Gradient Electrophoresis (TTGE),        Zn(II)-cyclen polyacrylamide gel electrophoresis, homogeneous        fluorescent PCR-based single nucleotide polymorphism analysis,        phosphate-affinity polyacrylamide gel electrophoresis,        high-throughput SNP genotyping platforms, molecular beacons,        5′nuclease reaction, Taqman assay, MassArray (single base primer        extension coupled with matrix-assisted laser        desorption/ionization time-of-flight mass spectrometry), trityl        mass tags, genotyping platforms (such as the Invader Assay®),        single base primer extension (SBE) assays, PCR amplification        (e.g. PCR amplification on magnetic nanoparticles (MNPs),        restriction enzyme analysis of PCR products (RFLP methods),        allele-specific PCR, multiple primer extension (MPEX), and        isothermal smart amplification. In another embodiment, at least        one polymorphism is detected by amplification of a target region        containing at least one polymorphism, and hybridization with at        least one sequence-specific oligonucleotide that hybridizes        under stringent conditions to at least one polymorphism and        detecting the hybridization. In another embodiment, the presence        of one or two alleles of the G genotype at the SNP rs4698775,        SNP rs17440077, SNP rs1329428, SNP rs429608 or SNP rs2230199 or        one or two alleles of the A genotype at the SNP rs10737680 in a        patient indicates an increased likelihood of response to        anti-factor D antibody treatment. In another embodiment, a        polymorphism that is in linkage disequilibrium with at least one        single nucleotide polymorphism selected from the group        consisting of single nucleotide polymorphism (SNP) rs4698775,        rs17440077, rs10737680, rs1329428, rs429608, and rs2230199 is        detected. In another embodiment, the degenerative disease is age        related macular degeneration. In another embodiment, the age        related macular degeneration is early, intermediate or advanced        AMD. In another embodiment, the advanced AMD is geographic        atrophy. In another embodiment, the anti-factor D antibody, or        antigen-binding fragment thereof is lampalizumab.

The invention further includes a method of assessing degenerativedisease in an individual, the method comprising:

-   -   (a) determining the presence of at least one degenerative        disease-associated polymorphism in a sample from the patient;        -   (i) by providing a nucleic acid sample from the patient;        -   (ii) genotyping the presence of at least one degenerative            disease-associated polymorphism wherein the polymorphism is            a risk allele, selected from the group consisting of a CFI            allele, a CFH allele, a C2 allele, a CFB allele, or a C3            allele;    -   (b) providing an assessment of degenerative disease when at        least one risk allele, selected from the group consisting of a        CFI allele, a CFH allele, a C2 allele, a CFB allele, or a C3        allele is present in the sample from the individual. In one        embodiment, the CFI allele is an equivalent allele thereof, the        CFH allele is an equivalent allele thereof, the C2 allele is an        equivalent allele thereof, the CFB allele is an equivalent        allele thereof, or the C3 allele is an equivalent allele        thereof. In another embodiment, the CFI allele comprises a G at        the single nucleotide polymorphism (SNP) rs4698775 or        rs17440077, the CFH allele comprises an A at the single        nucleotide polymorphism (SNP) rs10737680 or a G at the single        nucleotide polymorphism (SNP) rs1329428, the C2 allele comprises        a G at the single nucleotide polymorphism (SNP) rs429608, the        CFB allele comprises a G at the single nucleotide polymorphism        (SNP) rs429608, and the C3 allele comprises a G at the single        nucleotide polymorphism (SNP) rs2230199. In another embodiment,        the sample is a blood sample, saliva, cheek swab, tissue sample        or a sample of a bodily fluid. In another embodiment, the        nucleic acid sample comprises DNA. In another embodiment, the        nucleic acid sample comprises RNA. In another embodiment, the        nucleic acid sample is amplified. In another embodiment, the        nucleic acid sample is amplified by a polymerase chain reaction.        In another embodiment, at least one polymorphism is detected by        polymerase chain reaction. In another embodiment, at least one        polymorphism is detected by sequencing. In another embodiment,        at least one polymorphism is detected by a technique selected        from the group consisting of scanning probe and nanopore DNA        sequencing, pyrosequencing, Denaturing Gradient Gel        Electrophoresis (DGGE), Temporal Temperature Gradient        Electrophoresis (TTGE), Zn(II)-cyclen polyacrylamide gel        electrophoresis, homogeneous fluorescent PCR-based single        nucleotide polymorphism analysis, phosphate-affinity        polyacrylamide gel electrophoresis, high-throughput SNP        genotyping platforms, molecular beacons, 5′nuclease reaction,        Taqman assay, MassArray (single base primer extension coupled        with matrix-assisted laser desorption/ionization time-of-flight        mass spectrometry), trityl mass tags, genotyping platforms (such        as the Invader Assay®), single base primer extension (SBE)        assays, PCR amplification (e.g. PCR amplification on magnetic        nanoparticles (MNPs), restriction enzyme analysis of PCR        products (RFLP methods), allele-specific PCR, multiple primer        extension (MPEX), and isothermal smart amplification. In another        embodiment, at least one polymorphism is detected by        amplification of a target region containing at least one        polymorphism, and hybridization with at least one        sequence-specific oligonucleotide that hybridizes under        stringent conditions to at least one polymorphism and detecting        the hybridization. In another embodiment, a patient having one        or two alleles of the G genotype at the SNP rs4698775, SNP        rs17440077, SNP rs1329428, SNP rs429608 or SNP rs2230199 or one        or two alleles of the A genotype at the SNP rs10737680 is more        likely to respond to anti-factor D antibody treatment. In        another embodiment, a polymorphism that is in linkage        disequilibrium with at least one single nucleotide polymorphism        selected from the group consisting of single nucleotide        polymorphism (SNP) rs4698775, rs17440077, rs10737680, rs1329428,        rs429608, and rs2230199 is detected. In another embodiment, the        degenerative disease is age related macular degeneration. In        another embodiment, the age related macular degeneration is        early, intermediate or advanced AMD. In another embodiment, the        advanced AMD is geographic atrophy.

The invention further includes a method of identifying an individual whohas an increased risk for developing more advanced forms of age relatedmacular degeneration, the method comprising:

-   -   (a) determining the presence of at least one degenerative        disease-associated polymorphism in a sample from the individual;        -   (i) by providing a nucleic acid sample from the individual;        -   (ii) genotyping the presence of at least one degenerative            disease-associated polymorphism wherein the polymorphism is            a risk allele, selected from the group consisting of a CFI            allele, a CFH allele, a C2 allele, a CFB allele, or a C3            allele;    -   (b) identifying the individual as more likely to develop more        advanced forms of AMD when at least one risk allele, selected        from the group consisting of a CFI allele, a CFH allele, a C2        allele, a CFB allele, or a C3 allele is present. In one        embodiment, the individual is more likely to respond to a        therapy comprising anti-factor D antibody, or an antigen-binding        fragment thereof, when at least one risk allele, selected from        the group consisting of a CFI allele, a CFH allele, a C2 allele,        a CFB allele, or a C3 allele is present; and further comprises        selecting the therapy comprising anti-factor D antibody, or        antigen-binding fragment thereof In another embodiment, the CFI        allele is an equivalent allele thereof, the CFH allele is an        equivalent allele thereof, the C2 allele is an equivalent allele        thereof, the CFB allele is an equivalent allele thereof, or the        C3 allele is an equivalent allele thereof. In another        embodiment, the CFI allele comprises a G at the single        nucleotide polymorphism (SNP) rs4698775 or rs17440077, the CFH        allele comprises an A at the single nucleotide polymorphism        (SNP) rs10737680 or a G at the single nucleotide polymorphism        (SNP) rs1329428, the C2 allele comprises a G at the single        nucleotide polymorphism (SNP) rs429608, the CFB allele comprises        a G at the single nucleotide polymorphism (SNP) rs429608, and        the C3 allele comprises a G at the single nucleotide        polymorphism (SNP) rs2230199. In another embodiment, the sample        is a blood sample, saliva, cheek swab, tissue sample or a sample        of a bodily fluid. In another embodiment, the nucleic acid        sample comprises DNA. In another embodiment, the nucleic acid        sample comprises RNA. In another embodiment, the nucleic acid        sample is amplified. In another embodiment, the nucleic acid        sample is amplified by a polymerase chain reaction. In another        embodiment, at least one polymorphism is detected by polymerase        chain reaction. In another embodiment, at least one polymorphism        is detected by sequencing. In another embodiment, at least one        polymorphism is detected by a technique selected from the group        consisting of scanning probe and nanopore DNA sequencing,        pyrosequencing, Denaturing Gradient Gel Electrophoresis (DGGE),        Temporal Temperature Gradient Electrophoresis (TTGE),        Zn(II)-cyclen polyacrylamide gel electrophoresis, homogeneous        fluorescent PCR-based single nucleotide polymorphism analysis,        phosphate-affinity polyacrylamide gel electrophoresis,        high-throughput SNP genotyping platforms, molecular beacons,        5′nuclease reaction, Taqman assay, MassArray (single base primer        extension coupled with matrix-assisted laser        desorption/ionization time-of-flight mass spectrometry), trityl        mass tags, genotyping platforms (such as the Invader Assay®),        single base primer extension (SBE) assays, PCR amplification        (e.g. PCR amplification on magnetic nanoparticles (MNPs),        restriction enzyme analysis of PCR products (RFLP methods),        allele-specific PCR, multiple primer extension (MPEX), and        isothermal smart amplification. In another embodiment, at least        one polymorphism is detected by amplification of a target region        containing at least one polymorphism, and hybridization with at        least one sequence-specific oligonucleotide that hybridizes        under stringent conditions to at least one polymorphism and        detecting the hybridization. In another embodiment, a patient        having one or two alleles of the G genotype at the SNP        rs4698775, SNP rs17440077, SNP rs1329428, SNP rs429608 or SNP        rs2230199 or one or two alleles of the A genotype at the SNP        rs10737680 is more likely to respond to anti-factor D antibody        treatment. In another embodiment, a polymorphism that is in        linkage disequilibrium with at least one single nucleotide        polymorphism selected from the group consisting of single        nucleotide polymorphism (SNP) rs4698775, rs17440077, rs10737680,        rs1329428, rs429608, and rs2230199 is detected. In another        embodiment, the degenerative disease is age related macular        degeneration. In another embodiment, the age related macular        degeneration is early, intermediate or advanced AMD. In another        embodiment, the advanced AMD is geographic atrophy. In another        embodiment, the anti-factor D antibody, or antigen-binding        fragment thereof is lampalizumab.

The invention further includes a method of predicting progression of AMDin an individual, the method comprising:

-   -   (a) determining the presence of at least one degenerative        disease-associated polymorphism in a sample from the individual;        -   (i) by providing a nucleic acid sample from the individual;        -   (ii) genotyping the presence of at least one degenerative            disease-associated polymorphism wherein the polymorphism is            a risk allele, selected from the group consisting of a CFI            allele, a CFH allele, a C2 allele, a CFB allele, or a C3            allele;    -   (b) identifying the individual as more likely to develop more        advanced forms of AMD when at least one risk allele, selected        from the group consisting of a CFI allele, a CFH allele, a C2        allele, a CFB allele, or a C3 allele is present. In one        embodiment, the individual is more likely to respond to a        therapy comprising anti-factor D antibody, or an antigen-binding        fragment thereof, when at least one risk allele, selected from        the group consisting of a CFI allele, a CFH allele, a C2 allele,        a CFB allele, or a C3 allele is present; and further comprises        selecting the therapy comprising anti-factor D antibody, or        antigen-binding fragment thereof In another embodiment, the CFI        allele is an equivalent allele thereof, the CFH allele is an        equivalent allele thereof, the C2 allele is an equivalent allele        thereof, the CFB allele is an equivalent allele thereof, or the        C3 allele is an equivalent allele thereof. In another        embodiment, the CFI allele comprises a G at the single        nucleotide polymorphism (SNP) rs4698775 or rs17440077, the CFH        allele comprises an A at the single nucleotide polymorphism        (SNP) rs10737680 or a G at the single nucleotide polymorphism        (SNP) rs1329428, the C2 allele comprises a G at the single        nucleotide polymorphism (SNP) rs429608, the CFB allele comprises        a G at the single nucleotide polymorphism (SNP) rs429608, and        the C3 allele comprises a G at the single nucleotide        polymorphism (SNP) rs2230199. In another embodiment, the sample        is a blood sample, saliva, cheek swab, tissue sample or a sample        of a bodily fluid. In another embodiment, the nucleic acid        sample comprises DNA. In another embodiment, the nucleic acid        sample comprises RNA. In another embodiment, the nucleic acid        sample is amplified. In another embodiment, the nucleic acid        sample is amplified by a polymerase chain reaction. In another        embodiment, at least one polymorphism is detected by polymerase        chain reaction. In another embodiment, at least one polymorphism        is detected by sequencing. In another embodiment, at least one        polymorphism is detected by a technique selected from the group        consisting of scanning probe and nanopore DNA sequencing,        pyrosequencing, Denaturing Gradient Gel Electrophoresis (DGGE),        Temporal Temperature Gradient Electrophoresis (TTGE),        Zn(II)-cyclen polyacrylamide gel electrophoresis, homogeneous        fluorescent PCR-based single nucleotide polymorphism analysis,        phosphate-affinity polyacrylamide gel electrophoresis,        high-throughput SNP genotyping platforms, molecular beacons,        5′nuclease reaction, Taqman assay, MassArray (single base primer        extension coupled with matrix-assisted laser        desorption/ionization time-of-flight mass spectrometry), trityl        mass tags, genotyping platforms (such as the Invader Assay®),        single base primer extension (SBE) assays, PCR amplification        (e.g. PCR amplification on magnetic nanoparticles (MNPs),        restriction enzyme analysis of PCR products (RFLP methods),        allele-specific PCR, multiple primer extension (MPEX), and        isothermal smart amplification. In another embodiment, at least        one polymorphism is detected by amplification of a target region        containing at least one polymorphism, and hybridization with at        least one sequence-specific oligonucleotide that hybridizes        under stringent conditions to at least one polymorphism and        detecting the hybridization. In another embodiment, a patient        having one or two alleles of the G genotype at the SNP        rs4698775, SNP rs17440077, SNP rs1329428, SNP rs429608 or SNP        rs2230199 or one or two alleles of the A genotype at the SNP        rs10737680 is more likely to respond to anti-factor D antibody        treatment. In another embodiment, a polymorphism that is in        linkage disequilibrium with at least one single nucleotide        polymorphism selected from the group consisting of single        nucleotide polymorphism (SNP) rs4698775, rs17440077, rs10737680,        rs1329428, rs429608, and rs2230199 is detected. In another        embodiment, the degenerative disease is age related macular        degeneration. In another embodiment, the age related macular        degeneration is early, intermediate or advanced AMD. In another        embodiment, the advanced AMD is geographic atrophy. In another        embodiment, the anti-factor D antibody, or antigen-binding        fragment thereof is lampalizumab.

The invention includes a method for determining a degenerative diseaseindividual's risk for progression of degenerative disease comprising:

-   -   (a) detecting the presence of at least one degenerative        disease-associated polymorphism in a sample of the individual,        -   (i) by providing a nucleic acid sample from the individual;        -   (ii) genotyping the presence of at least one degenerative            disease-associated polymorphism wherein the polymorphism is            a risk allele selected from the group consisting of a CFI            risk allele, a CFH risk allele, a C2 risk allele, a CFB risk            allele or a C3 risk allele;    -   (b) identifying the individual as having increased risk for        degenerative disease progression when the risk allele        polymorphism is present wherein the increased risk is relative        to the risk when the major allele of the polymorphism is        present. In one embodiment, the CFI allele is an equivalent        allele thereof, the CFH allele is an equivalent allele thereof,        the C2 allele is an equivalent allele thereof, the CFB allele is        an equivalent allele thereof, or the C3 allele is an equivalent        allele thereof. In another embodiment, the CFI allele comprises        a G at the single nucleotide polymorphism (SNP) rs4698775 or        rs17440077, the CFH allele comprises an A at the single        nucleotide polymorphism (SNP) rs10737680 or a G at the single        nucleotide polymorphism (SNP) rs1329428, the C2 allele comprises        a G at the single nucleotide polymorphism (SNP) rs429608, the        CFB allele comprises a G at the single nucleotide polymorphism        (SNP) rs429608, and the C3 allele comprises a G at the single        nucleotide polymorphism (SNP) rs2230199. In another embodiment,        the sample is a blood sample, saliva, cheek swab, tissue sample        or a sample of a bodily fluid. In another embodiment, the        nucleic acid sample comprises DNA. In another embodiment, the        nucleic acid sample comprises RNA. In another embodiment, the        nucleic acid sample is amplified. In another embodiment, the        nucleic acid sample is amplified by a polymerase chain reaction.        In another embodiment, at least one polymorphism is detected by        polymerase chain reaction. In another embodiment, at least one        polymorphism is detected by sequencing. In another embodiment,        at least one polymorphism is detected by a technique selected        from the group consisting of scanning probe and nanopore DNA        sequencing, pyrosequencing, Denaturing Gradient Gel        Electrophoresis (DGGE), Temporal Temperature Gradient        Electrophoresis (TTGE), Zn(II)-cyclen polyacrylamide gel        electrophoresis, homogeneous fluorescent PCR-based single        nucleotide polymorphism analysis, phosphate-affinity        polyacrylamide gel electrophoresis, high-throughput SNP        genotyping platforms, molecular beacons, 5′nuclease reaction,        Taqman assay, MassArray (single base primer extension coupled        with matrix-assisted laser desorption/ionization time-of-flight        mass spectrometry), trityl mass tags, genotyping platforms (such        as the Invader Assay®), single base primer extension (SBE)        assays, PCR amplification (e.g. PCR amplification on magnetic        nanoparticles (MNPs), restriction enzyme analysis of PCR        products (RFLP methods), allele-specific PCR, multiple primer        extension (MPEX), and isothermal smart amplification. In another        embodiment, at least one polymorphism is detected by        amplification of a target region containing at least one        polymorphism, and hybridization with at least one        sequence-specific oligonucleotide that hybridizes under        stringent conditions to at least one polymorphism and detecting        the hybridization. In another embodiment, the presence of two        alleles of the G genotype at the SNP rs4698775, SNP rs17440077,        SNP rs1329428, SNP rs429608 or SNP rs2230199 or one or two        alleles of the A genotype at the SNP rs10737680 in the        individual indicates an increased risk for degenerative disease        progression. In another embodiment, a polymorphism that is in        linkage disequilibrium with at least one single nucleotide        polymorphism selected from the group consisting of single        nucleotide polymorphism (SNP) rs4698775, rs17440077, rs10737680,        rs1329428, rs429608, and rs2230199 is detected. In another        embodiment, the degenerative disease is age related macular        degeneration. In another embodiment, the age related macular        degeneration is early, intermediate or advanced AMD. In another        embodiment, the advanced AMD is geographic atrophy.

The invention includes a method of treating a degenerative diseasecomprising administering an anti-factor D antibody, or antigen-bindingfragment thereof, comprising HVRH1, HVRH2, HVRH3, HVRL1, HVRL2, HVRL3,and HVRL3, wherein the respective HVRs have the amino acid sequence ofSEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5 andSEQ ID NO: 6 to a patient suffering from a degenerative disease in a 10mg dose every month. In one embodiment, the age related maculardegeneration is early, intermediate or advanced AMD. In anotherembodiment, the advanced AMD is geographic atrophy. In anotherembodiment, a second medicament is administered. In another embodiment,the second medicament is a VEGF inhibitor. In another embodiment, theVEGF inhibitor is ranibizumab. In another embodiment, the anti-factor Dantibody, or antigen binding fragment thereof, is an antibody or antigenbinding fragment thereof comprising a VH comprising SEQ II) NO: 7 and aVL comprising SEQ ID NO: 8. In another embodiment, the treatment resultsin a greater than or equal to 20% reduction of change in GA area frombaseline GA area. In another embodiment, the treatment results in agreater than or equal to 15% reduction of change in GA area frombaseline GA area. In another embodiment, the treatment results in agreater than or equal to 10% reduction of change in GA area frombaseline GA area. In another embodiment, the treatment results in agreater than or equal to 5% reduction of change in GA area from baselineGA area. In another embodiment, the patient has geographic atrophysecondary to AMD In another embodiment, the study eye in the patient hasa BCVA between 20/25 and 20/400. In another embodiment, the study eye inthe patient has a BCVA between 20/25 and 20/100. In another embodiment,the study eye in the patient has a BCVA between 20/50 and 20/400. Inanother embodiment, the study eye in the patient has a BCVA better than20/25 or worse than 20/400. In another embodiment, the patient has notreceived any previous intravitreal treatment, retinal surgery or otherretinal therapeutic procedures in the study eye.

The invention includes a kit for genotyping in a biological sample froma degenerative disease patient, wherein the kit comprisesoligonucleotides for polymerase chain reaction or sequencing fordetection of a risk allele. In one embodiment, the biological sample isa blood sample, saliva, cheek swab, tissue sample or a sample of bodilyfluids. In another embodiment, the biological sample is a nucleic acidsample. In another embodiment, the nucleic acid sample comprises DNA. Inanother embodiment, the nucleic acid sample comprises RNA. In anotherembodiment, the nucleic acid sample is amplified. In another embodiment,the kit further comprises a package insert for determining whether adegenerative disease patient is likely to respond to an anti-factor Dantibody, or antigen binding fragment thereof. In another embodiment,the kit is used to detect the presence of a CFI risk allele, a CFH riskallele, a C2 risk allele, a CFB risk allele or a C3 risk allele. Inanother embodiment, the kit is used to detect the presence of one or twoalleles of the G genotype at the SNP rs4698775, SNP rs17440077, SNPrs1329428, SNP rs429608 or SNP rs2230199 or two alleles of the Agenotype at the SNP rs10737680.

The invention includes a kit for predicting whether a patient has anincreased likelihood of benefiting from treatment with an anti-factor Dantibody or antigen binding fragment thereof comprising a firstoligonucleotide and a second oligonucleotide specific for a polymorphismin CFI, C2 , CFB, C3 or CFH. In one embodiment, said firstoligonucleotide and said second oligonucleotide may be used to amplify aregion of the CFI, C2 , CFB, C3 or CFH gene comprising a polymorphism inCFI, C2 , CFB, C3 or CFH respectively, selected from the groupconsisting of the G genotype at the SNP rs4698775, SNP rs17440077, SNPrs1329428, SNP rs429608 or SNP rs2230199 or the A genotype at the SNPrs10737680. In another embodiment, the anti-factor D antibody, orantigen-binding fragment thereof, comprises HVRH1, HVRH2, HVRH3, HVRL1,HVRL2, HVRL3, and HVRL3, wherein the respective HVRs have the amino acidsequence of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQID NO: 5 and SEQ ID NO: 6. In another embodiment, the anti-factor Dantibody, or antigen-binding fragment thereof, comprises the variableheavy chain of SEQ ID NO: 7 and/or the variable light chain of SEQ IDNO: 8. In another embodiment, the polymorphism is a CFI polymorphism. Inanother embodiment, the CFI polymorphism is present in combination withone or more additional polymorphisms selected from the group consistingof a CFH polymorphism, a C2 polymorphism, a C3 polymorphism or a CFBpolymorphism.

The invention includes use of an agent that specifically binds to atleast one degenerative disease-associated polymorphism wherein thepolymorphism is a risk allele selected from the group consisting of aCFI risk allele, a CFH risk allele, a C2 risk allele, a CFB risk alleleor a C3 risk allele for the manufacture of a diagnostic for diagnosing adegenerative disease. In one embodiment, the CFI allele is an equivalentallele thereof, the CFH allele is an equivalent allele thereof, the C2allele is an equivalent allele thereof, the CFB allele is an equivalentallele thereof, or the C3 allele is an equivalent allele thereof. Inanother embodiment, the CFI allele comprises a G at the singlenucleotide polymorphism (SNP) rs4698775 or rs17440077, the CFH allelecomprises an A at the single nucleotide polymorphism (SNP) rs10737680 ora G at the single nucleotide polymorphism (SNP) rs1329428, the C2 allelecomprises a G at the single nucleotide polymorphism (SNP) rs429608, theCFB allele comprises a G at the single nucleotide polymorphism (SNP)rs429608, and the C3 allele comprises a G at the single nucleotidepolymorphism (SNP) rs2230199. In another embodiment, at least onepolymorphism is detected by a technique selected from the groupconsisting of scanning probe and nanopore DNA sequencing,pyrosequencing, Denaturing Gradient Gel Electrophoresis (DGGE), TemporalTemperature Gradient Electrophoresis (TTGE), Zn(II)-cyclenpolyacrylamide gel electrophoresis, homogeneous fluorescent PCR-basedsingle nucleotide polymorphism analysis, phosphate-affinitypolyacrylamide gel electrophoresis, high-throughput SNP genotypingplatforms, molecular beacons, 5′nuclease reaction, Taqman assay,MassArray (single base primer extension coupled with matrix-assistedlaser desorption/ionization time-of-flight mass spectrometry), tritylmass tags, genotyping platforms (such as the Invader Assay®), singlebase primer extension (SBE) assays, PCR amplification (e.g. PCRamplification on magnetic nanoparticles (MNPs), restriction enzymeanalysis of PCR products (RFLP methods), allele-specific PCR, multipleprimer extension (MPEX), and isothermal smart amplification. In anotherembodiment, at least one polymorphism is detected by amplification of atarget region containing at least one polymorphism, and hybridizationwith at least one sequence-specific oligonucleotide that hybridizesunder stringent conditions to at least one polymorphism and detectingthe hybridization. In another embodiment, the presence of one or twoalleles of the G genotype at the SNP rs4698775, SNP rs17440077, SNPrs1329428, SNP rs429608 or SNP rs2230199 or one or two alleles of the Agenotype at the SNP rs10737680 in the individual indicates an increasedrisk for degenerative disease progression. In another embodiment, apolymorphism that is in linkage disequilibrium with at least one singlenucleotide polymorphism selected from the group consisting of singlenucleotide polymorphism (SNP) rs4698775, rs17440077, rs10737680,rs1329428, rs429608, and rs2230199 is detected. In another embodiment,the degenerative disease is age related macular degeneration. In anotherembodiment, the age related macular degeneration is early, intermediateor advanced AMD. In another embodiment, the advanced AMD is geographicatrophy.

The invention includes in vitro use of an agent that binds to at leastone degenerative disease-associated polymorphism wherein thepolymorphism is a risk allele selected from the group consisting of aCFI risk allele, a CFH risk allele, a C2 risk allele, a CFB risk alleleor a C3 risk allele for identifying a patient having a degenerativedisease likely to respond to a therapy comprising an anti-factor Dantibody, or antigen binding fragment thereof, wherein the presence ofsaid polymorphisms identifies that the patient is more likely to respondto the therapy. In one embodiment, the CFI allele is an equivalentallele thereof, the CFH allele is an equivalent allele thereof, the C2allele is an equivalent allele thereof, the CFB allele is an equivalentallele thereof, or the C3 allele is an equivalent allele thereof. Inanother embodiment, the CFI allele comprises a G at the singlenucleotide polymorphism (SNP) rs4698775 or rs17440077, the CFH allelecomprises an A at the single nucleotide polymorphism (SNP) rs10737680 ora G at the single nucleotide polymorphism (SNP) rs1329428, the C2 allelecomprises a G at the single nucleotide polymorphism (SNP) rs429608, theCFB allele comprises a G at the single nucleotide polymorphism (SNP)rs429608, and the C3 allele comprises a G at the single nucleotidepolymorphism (SNP) rs2230199. In another embodiment, at least onepolymorphism is detected by a technique selected from the groupconsisting of scanning probe and nanopore DNA sequencing,pyrosequencing, Denaturing Gradient Gel Electrophoresis (DGGE), TemporalTemperature Gradient Electrophoresis (TTGE), Zn(II)-cyclenpolyacrylamide gel electrophoresis, homogeneous fluorescent PCR-basedsingle nucleotide polymorphism analysis, phosphate-affinitypolyacrylamide gel electrophoresis, high-throughput SNP genotypingplatforms, molecular beacons, 5′nuclease reaction, Taqman assay,MassArray (single base primer extension coupled with matrix-assistedlaser desorption/ionization time-of-flight mass spectrometry), tritylmass tags, genotyping platforms (such as the Invader Assay®), singlebase primer extension (SBE) assays, PCR amplification (e.g. PCRamplification on magnetic nanoparticles (MNPs), restriction enzymeanalysis of PCR products (RFLP methods), allele-specific PCR, multipleprimer extension (MPEX), and isothermal smart amplification. In anotherembodiment, at least one polymorphism is detected by amplification of atarget region containing at least one polymorphism, and hybridizationwith at least one sequence-specific oligonucleotide that hybridizesunder stringent conditions to at least one polymorphism and detectingthe hybridization. In another embodiment, the presence of one or twoalleles of the G genotype at the SNP rs4698775, SNP rs17440077, SNPrs1329428, SNP rs429608 or SNP rs2230199 or one or two alleles of the Agenotype at the SNP rs10737680 in the individual indicates an increasedrisk for degenerative disease progression. In another embodiment, apolymorphism that is in linkage disequilibrium with at least one singlenucleotide polymorphism selected from the group consisting of singlenucleotide polymorphism (SNP) rs4698775, rs17440077, rs10737680,rs1329428, rs429608, and rs2230199 is detected. In another embodiment,the degenerative disease is age related macular degeneration. In anotherembodiment, the age related macular degeneration is early, intermediateor advanced AMD. In another embodiment, the advanced AMD is geographicatrophy.

The invention includes in vitro use of a degenerative disease-associatedpolymorphism for selecting a patient having a degenerative disease aslikely to respond to a therapy comprising anti-factor D or anantigen-binding fragment thereof, wherein the patient is identified asbeing more likely to respond to the therapy when the degenerativedisease-associated polymorphism is detected in the sample from thepatient. In one embodiment, the degenerative disease-associatedpolymorphism is an AMD-associated polymorphism. In another embodiment,the polymorphisms is a risk allele selected from the group consisting ofa CFI risk allele, a CFH risk allele, a C2 risk allele, a CFB riskallele or a C3 risk allele for the manufacture of a diagnostic fordiagnosing a degenerative disease. In another embodiment, the CFI alleleis an equivalent allele thereof, the CFH allele is an equivalent allelethereof, the C2 allele is an equivalent allele thereof, the CFB alleleis an equivalent allele thereof, or the C3 allele is an equivalentallele thereof In another embodiment, the CFI allele comprises a G atthe single nucleotide polymorphism (SNP) rs4698775 or rs17440077, theCFH allele comprises an A at the single nucleotide polymorphism (SNP)rs10737680 or a G at the single nucleotide polymorphism (SNP) rs1329428,the C2 allele comprises a G at the single nucleotide polymorphism (SNP)rs429608, the CFB allele comprises a G at the single nucleotidepolymorphism (SNP) rs429608, and the C3 allele comprises a G at thesingle nucleotide polymorphism (SNP) rs2230199.

The invention includes the use of a degenerative disease-associatedpolymorphism for the manufacture of a diagnostic for assessing thelikelihood of a response of a patient having a degenerative disease to atherapy comprising an anti-factor D antibody, or antigen-bindingfragment thereof. In one embodiment, the degenerative disease-associatedpolymorphism is an AMD-associated polymorphism. In another embodiment,the polymorphisms is a risk allele selected from the group consisting ofa CFI risk allele, a CFH risk allele, a C2 risk allele, a CFB riskallele or a C3 risk allele for the manufacture of a diagnostic fordiagnosing a degenerative disease. In another embodiment, the CFI alleleis an equivalent allele thereof, the CFH allele is an equivalent allelethereof, the C2 allele is an equivalent allele thereof, the CFB alleleis an equivalent allele thereof, or the C3 allele is an equivalentallele thereof. In another embodiment, the CFI allele comprises a G atthe single nucleotide polymorphism (SNP) rs4698775 or rs17440077, theCFH allele comprises an A at the single nucleotide polymorphism (SNP)rs10737680 or a G at the single nucleotide polymorphism (SNP) rs1329428,the C2 allele comprises a G at the single nucleotide polymorphism (SNP)rs429608, the CFB allele comprises a G at the single nucleotidepolymorphism (SNP) rs429608, and the C3 allele comprises a G at thesingle nucleotide polymorphism (SNP) rs2230199:

In certain embodiments, a detection, preventative and/or treatmentregimen is specifically prescribed and/or administered to individualswho will most benefit from it based upon their risk of AMD progressionto more advanced AMD (e.g. intermediate AMD or CNV or geographicatrophy), as assessed by the methods described herein. Methods are thusprovided for identifying a patient at risk of AMD progression and thenprescribing detection, therapeutic or preventative regime to individualsidentified as being at increased risk of AMD progression. The certainembodiments are directed to for treating AMD in a subject, reducingprogression of AMD in a subject, or early detection of AMD progressionin a subject, which comprise: detecting the presence or absence of apolymorphic variant associated with AMD or AMD progression at a SNP in anucleotide sequence (includes SNP rs4698775, rs17440077, rs10737680,rs1329428, rs429608, rs2230199) (Genome Reference Consortium GRCh37;UCSC Genome HG19 Assembly; February 2009), and prescribing oradministering an AMD treatment regimen, preventative regimen and/ordetection regimen to a subject from whom the sample originated whereinthe presence of the polymorphic variant associated with AMD orprogression of AMD are detected at one or more SNPs in the nucleotidesequence. In these methods, genetic results may be utilized incombination with other test results to diagnose AMD or AMD progression,as described herein.

In other embodiments, pharmacogenomics methods may be used to analyzeand predict a response to an AMD treatment or drug. If thepharmacogenomics analysis indicates a likelihood that an individual willrespond positively to an AMD treatment with a particular drug (e.g.anti-factor D antibody, or antigen-binding fragment thereof), the drugmay be administered to the individual. If the analysis indicates that anindividual is likely to respond negatively to treatment with aparticular drug, an alternative course of treatment may be prescribed. Anegative response may be defined as either absence of an efficaciousresponse or the presence of toxic side effects. The response to atherapeutic treatment can be predicted in a background study in whichsubjects in any of the following populations, but not limited to thefollowing populations, are genotyped: a population that respondsfavorably to a treatment regimen, a population that does not respondsignificantly to a treatment regimen, and a population that respondsadversely to a treatment regimen (e.g. exhibits one or more sideeffects). An individual may be genotyped to predict which populationthey fall into.

The methods described herein are also applicable to clinical drugtrials. Polymorphic variants indicative of response to an agent fortreating AMD or to side effects to an agent for treating AMD may beidentified at one or more SNPs. Thereafter, potential participants inclinical trials of such an agent may be screened to identify thoseindividuals most likely to respond favorably to the drug and to excludethose less likely to respond or to experience side effects. Accordingly,the efficacy of the treatment may be measured in individuals who respondpositively to the drug, without lowering the measurement as a result ofthe inclusion of individuals who are unlikely to respond positively tothe treatment. Thus, another embodiment is a method of selecting anindividual for inclusion in a clinical trial of a treatment comprisingthe steps of: (a) obtaining a nucleic acid sample for an individual, (b)determining the identity of a polymorphic variant which is associatedwith a positive response to the treatment, or a polymorphic variantwhich is associated with a negative response to the treatment and (c)including the individual in the clinical trial if the nucleic acidsample contains the polymorphic variant associated with a positiveresponse to the treatment. Step (c) can also include administering thetreatment to the individual if the nucleic acid sample contains thepolymorphic variant that is associated with a positive response to thetreatment and/or if the nucleic acid sample lacks the polymorphicvariant associated with a negative response to the treatment.

Further details of the invention are illustrated by the followingnon-limiting Examples. The disclosures of all citations in thespecification are expressly incorporated herein by reference.

EXAMPLES Example 1 Geographic Atrophy Clinical Study

1. Summary

A Phase 1b/II, randomized, single-masked, sham injection—controlledmulticenter study was carried out to evaluate the safety, tolerabilityand evidence of activity of lampalizumab intravitreal (ITV) injectionsadministered monthly or every other month for an 18-month treatmentperiod in patients with geographic atrophy (GA). The randomized studywas preceded by a safety run-in assessment. Primary, secondary andexploratory outcomes were assessed at the conclusion of the 18-monthtreatment period. A 3-month safety follow-up period commenced afteradministration of the final ITV or sham injection for study patients whodid not qualify or chose not to continue into the open-label extensionstudy (OLE). For the safety run-in assessment, multiple monthlyadministrations with 10 mg of lampalizumab ITV was conducted prior toinitiating enrollment in the randomized phase of the study. All patientsin the safety run-in assessment received a minimum of 3 monthly doses oflampalizumab to obtain safety data from 10 evaluable patients. Anevaluable patient was a patient that had received at least three studydrug injections.

For the four-arm randomized phase, patients were randomized using aninteractive web response system (IWRS) in a ratio of drug to shamallocation of 2:1:2:1 so that 43 patients received a lampalizumabinjection monthly, 21 patients received a sham injection monthly for atotal of 18 injections, 44 patients received a lampalizumab injectionevery other month, and 21 patients received a sham injection every othermonth for a total of 9 injections.

A summary of the trial design is in Table 2.

TABLE 2 Design Randomized, single-masked, sham injection controlled,single dose study to evaluate safety, tolerability and evidence ofactivity of Lampalizumab vs sham injection on geographic atrophy (GA)Population Patients had a diagnosis of GA secondary to AMD according toreading center evaluation and criteria Sample Size 129 patients wereenrolled; 123were in the efficacy-evaluable population Study Duration 18months (and 3 month safety follow-up) Schedule, Dose Intravitreal (IVT)formulation, monthly (Q4w) or every other month (Q8w), 1 active dose (10mg) 1° endpoint Growth rate of GA lesion area from baseline to month 18as measured by fundus autofluorescence (FAF) 2° endpoint Growth rate ofGA lesion area from baseline to month 18 as assessed by digitizedstereoscopic color fundus photographs (CFP) Mean change in BCVA frombaseline to month 18 using the ETDRS VA chart

Patient population in this study included 57% female and had a mean ageof 79. The majority of patients in this study were white (>98%) and werenot Hispanic or Latino (>98%). Demographics and baseline characteristicswere generally balanced across treatment groups. 58% of allefficacy-evaluable patients had baseline geographic atrophy lesion area<4DA (1DA=2.54 mm2), and the distribution across the treatment groupswas generally similar.

A run-in assessment of the safety and tolerability of multiple monthlyadministrations with 10 mg of lampalizumab ITV was conducted prior toinitiating enrollment in the randomized phase of the study. All patientsin the safety run-in assessment received a minimum of 3 monthly doses oflampalizumab (FIG. 1 to obtain safety data from 10 evaluable patients.An evaluable patient is a patient that received at least three studydrug injections. Patient eligibility and enrollment in the safety run-inassessment followed the process described for the randomized phase (seebelow) of the study with the exception of BCVA inclusion criteria (seebelow; 3.1.1.b.1)).

For the safety run-in assessment, each patient received study druginjection on Day 0 and was assessed on Day 1, Day 7 (±2), and Day 30(±7) after each injection until the start of the dosing hiatus. Afterthe tenth evaluable patient completed the Day 90 (±7) visit followingthe third study drug administration, a hiatus in dosing of approximately1 week ensued. During the hiatus, the safety and tolerability ofmultiple drug administration. The safety run-in assessment demonstratedacceptable safety and tolerability for the 10-mg dose of lampalizumab inaccordance with the dose-limiting criteria (DLC; see below), and therandomized phase was initiated. Following the hiatus and determinationof acceptable safety and tolerability for the 10 mg dose oflampalizumab, patients who participated in the safety run-in assessmentcontinued monthly study drug administration at the 10 mg. These patientsreceived a maximum of 18 lampalizumab treatments during the study.

Patients who were discontinued from the study treatment early wereencouraged to undergo the scheduled monthly assessments until completionof their study period. If monthly assessments were not possible,patients were evaluated at least every 3 months and completed the12-month and 18-month visits. Patients who were discontinued from thestudy treatment prematurely were not permitted to enter the OLE study.

Patients withdrawn from the study prior to completion were asked toreturn for an early termination evaluation 30 (±7) days following theirlast study treatment for monitoring of adverse events and the finalstudy visit assessments. Patients withdrawn from the study prior tocompletion were not permitted to enter the OLE study.

If ≥2 patients experienced the same dose-limiting toxicity (DLT) duringthe safety run-in assessment (e.g., ≥2 patients with vitritis that meetthe DLT criteria), then the 10-mg dosing cohort would have beensuspended, and all patients in this cohort would have been discontinuedfrom the study and the early termination evaluation process would havebeen followed. A new cohort would have been enrolled to obtain 10evaluable patients at the 5-mg dose; the same process and rules for thesafety run-in assessment would have applied to the patients in the 5-mgcohort as outlined for the 10-mg cohort. If the dose-reduction plan with5 mg was activated, successful completion of this cohort in accordancewith DLC would have been required to initiate the randomized phase (FIG.1).

Individual DLTs were defined as any of the following adverse events thatoccurred during the safety run-in assessment period and were believed tobe study drug-related:

-   -   1. Vitritis or uveitis, which was defined as a change of 2 units        on standard grading scales after the study drug injection        (grading scale for assessment of anterior chamber flare or cells        and vitreous cells). In accordance with this definition, study        exclusion criteria established a baseline grade of 0, and an        increase to 2+ or greater would have constituted a DLT. Anterior        chamber or vitreous cell count of Grade 4+ would have been        considered a major toxicity requiring interruption of enrollment        and further evaluation by the internal Safety Review Committee        to determine if further enrollment/treatment was appropriate    -   2. Endophthalmitis    -   3. Sustained elevation (measured on 3 consecutive scheduled        visits) of intraocular pressure (IOP)≥30 mmHg    -   4. Sustained loss (measured on 3 consecutive scheduled visits)        of visual acuity (VA) ≥15 letters after the study drug injection        that is not attributable to the injection procedure or        progression of GA

The safety run-in patients were assessed for DLTs after each study druginjection on Day 1, Day 7 (±2), and Day 30 (±7) visits. This regimen wascontinued until the tenth evaluable patient received the third studydrug injection and completed the Day 90 (±7) visit.

The study drug dose of 10 mg that demonstrated acceptable safety andtolerability in accordance with DLC defined in the safety run-inassessment was used for the randomized phase of the study. 129 patientswith GA secondary to AMD were enrolled in the randomized phase. Thestudy consisted of a screening period of up to 14 days (Days-14 to -1),and a treatment period of 18 months for all randomized patients, and a3-month safety follow-up period after the final study drug or shamadministration for patients who did not qualify or chose not to continueinto the open-label extension study.

A patient was required to satisfy all eligibility criteria at both thescreening and the Day 0 visits, including receipt of all screening visitimages by the central reading center. As part of the screening process,the central reading center evaluated fundus autofluorescence (FAF)images, digital fundus photographs (FP), and fluorescein angiograms (FA)to provide an objective, masked assessment of patient eligibilityregarding GA. Eligible patients were enrolled on Day 0 and randomizedusing an interactive web response system (IWRS) in a ratio of drug tosham allocation of 2:1:2:1 so that 43 patients received an lampalizumabinjection monthly, 21 patients received a sham injection monthly for atotal of 18 injections, 44 patients received an lampalizumab injectionevery other month, and 21 patients received a sham injection every othermonth for a total of 9 injections (FIG. 1). Eligible patients werestratified based on GA lesion size. Patients were enrolled on the sameday the treatment was to be initiated (Day 0).

Only one eye was chosen as the study eye. If both eyes were eligible,the eye with the worse vision (worse VA and/or least function) wasselected for study treatment (study eye). The investigators and othersite staff members were not masked to patients' treatment assignment.Only patients were masked to their treatment assignment. All patientshad scheduled monthly visits for the duration of the study. Enrolledpatients had the first ITV injection of lampalizumab or shamadministered by the investigator on Day 0. The randomized phase patientshad safety and ocular assessments performed 7 (±2) days after the firstinjection. At the subsequent visits (every month), patients in themonthly treatment arms had safety evaluations performed by theinvestigator prior to receiving study drug or sham injection. Patientsin the every-other-month treatment arms also had safety evaluationsperformed monthly but received study drug or sham only at theevery-other-month visit. Randomized phase patients were contacted bysite personnel 7 (±2) days after each injection to elicit reports ofdecrease in vision, eye pain, unusual redness, or any other new ocularsymptoms in the study eye. Patients were also asked to verify that theytook the prescribed, self-administered, post-injection antimicrobials.Patients who qualified and chose to continue into the OLE study had afinal safety visit at the Month 18 visit. Patients who did not qualifyor chose not to continue into the OLE study had a final safety visit atthe Month 19 visit (the every-other-month treatment arms), or at theMonth 20 visit (monthly treatment arms). Missed doses were not be madeup.

Patients who were prematurely discontinued from study treatment wereencouraged to undergo the scheduled monthly assessments until completionof their study period. If monthly assessments were not possible,patients were evaluated at least every 3 months and completed the12-month and 18-month visits. Patients who were prematurely discontinuedfrom study treatment were not permitted to continue to the OLE study.Patients withdrawn from the study prior to completion were asked toreturn for an early termination evaluation 30 (±7) days following theirlast study treatment for monitoring of adverse events and the finalstudy visit assessments. Patients withdrawn from the study prior tocompletion were not permitted to continue to the OLE study.

2. Outcome Measures

2.1 Primary Outcome Measure

The primary efficacy outcome for evidence of activity in the Phase 1b/IIstudy was an anatomic endpoint, growth rate of GA lesion area frombaseline to month 18 as measured by FAF. The anatomic primary endpointprovided a more sensitive metric of GA progression and served as asurrogate for vision loss.

2.2 Secondary Outcome Measures

The secondary efficacy outcome measure was growth rate of GA lesion areafrom baseline to month 18 as assessed by digitized stereoscopic colorfundus photographs and mean change in BCVA from baseline to month 18using the ETDRS VA chart.

2.3 Additional Outcome Measures

Additional exploratory outcome measures included the following: a)growth rate of GA area from baseline assessed by spectral domain-opticalcoherence tomography (SD-OCT); b) change in drusen volume assessed bySD-OCT; c) conversion rate to wet AMD in study eyes treated withlampalizumab versus sham control; d) change from baseline in the numberof words read per minute on the Submacular Surgery Trial (SST) ReadingSpeed assessment; (e) change from baseline in the number of words readper minute binocularly on the Minnesota Reading Speed Assessment(MNRead); (f) change from baseline in contrast sensitivity as measuredby the number of letters read correctly on the Pelli-Robson chart; (g)change from baseline in the National Eye Institute Visual FunctioningQuestionnaire-25 (NEI VFQ-25_composite score and the 12 subscale scores;(h) change from baseline in the Functional Reading Independence Index(FRII); (i) clinical genotyping to assess relationships between geneticpolymorphisms associated with AMD, disease characteristics, and responseto administration to lampalizumab.

2.4 Pharmacokinetic and Pharmacodynamic Outcome Measures

The PK profile from the serum concentration-time data followingadministration of lampalizumab was determined. Derived PK parametersincluded the following: (a) exposure after first dose (AUC); (b) maximumobserved serum concentration (C_(max)); (c) observed steady-state troughconcentration; (d) time to reach steady-state; and (e) accumulationratio based on trough concentration. Anterior chamber (aqueous humor)paracentesis samples were collected to assess PK and PD relationships.Additional PK and PD analysis were conducted.

2.5 Exploratory Outcome Measures

-   -   a. Growth rate of GA area from baseline assessed by spectral        domain-optical coherence tomography (SD-OCT)    -   b. Change in drusen volume assessed by SD-OCT    -   c. Conversion rate to wet AMD in study eyes treated with        lampalizumab versus sham control    -   d. Change from baseline in the number of words read per minute        on the Submacular Surgery Trial (SST) Reading Speed assessment    -   e. Change from baseline in the number of words read per minute        binocularly on the Minnesota Reading Speed Assessment (MNRead)    -   f. Change from baseline in contrast sensitivity as measured by        the number of letters read correctly on the Pelli-Robson chart    -   g. Change from baseline in the National Eye Institute Visual        Functioning Questionnaire-25 (NEI VFQ-25) composite score and        the 12 subscale scores    -   h. Change from baseline in the Functional Reading Independence        Index (FRII)    -   i. Clinical genotyping to assess relationships between genetic        polymorphisms associated with AMD, disease characteristics, and        response to administration of lampalizumab

2.5 Safety Plan

Potential safety issues associated with the route of administration orpharmacology of lampalizumab included decreased BCVA; conjunctivalhemorrhage; uveitis or vitritis (see the definitions of uveitis andvitritis in (defined above; grading scale for assessment of anteriorchamber flare or cells and vitreous cells for anterior chamber andvitreous inflammation grading scales); intraocular infection; transientand/or sustained elevation of IOP; cataract development or progression;retinal or intravitreal hemorrhage, macular edema; and retinal break ordetachment. The incidence of all adverse events (serious andnon-serious) were recorded on electronic Case Report Forms (eCRFs) forthe duration of this study.

Systemic levels of lampalizumab following multiple ITV administrationswere anticipated to be low. Nevertheless, patients were monitored forevidence of systemic inhibition of ACP activity such as loweredinfection threshold, particularly to encapsulated bacteria (i.e.,Neisseria meningitidis, Streptococcus pneumonia, and Haemophilusinfluenza).

The incidence and characteristics of adverse events, serious adverseevents, and laboratory abnormalities were assessed. Ongoing review ofsafety was performed.

Safety Run-In Phase: Prompt safety monitoring and review of post-studydrug treatment safety data was performed to determine whether the DLCare met. All DLTs occurring within prespecified window of study drugadministration was reported and the reports were reviewed.

After study drug injection on Day 0, all patients returned for safetyassessment visits on Day 1, Day 7 (±2), and Day 30 (±7) after eachmonthly injection until the start of the dosing hiatus. The identicalsafety assessments were performed for the safety run-in patients aslisted for the randomized phase patients below.

Randomized Phase: All patients returned for a safety assessment visit onDay 7 (±2 days) after the first injection. For subsequent injections,randomized patients were contacted by study site personnel 7 (±2) daysafter each injection to elicit reports of any decrease in vision, eyepain, unusual redness, or any other new ocular symptoms in the studyeye. Patients were asked whether they have taken the prescribed,self-administered, post-injection antimicrobials. Patients wereinstructed to contact the investigator at any time if they had anyhealth-related concerns. If warranted, patients were asked to return tothe clinic as soon as possible for a safety assessment visit.

A finger-counting test was conducted for each patient within 15 minutesfollowing study treatment by the physician; hand motion or lightperception was tested when necessary. Following the study treatment,patients remained at the clinic for at least 60 (±10) minutes.Intraocular pressure was measured bilaterally prior to treatment and 60(±10) minutes after study treatment for the study eye only. If there wasno safety concerns at 60 (±10) minutes, the patient was discharged fromthe clinic. If the IOP is increased by ≥10 mm Hg from the pre-injectionmeasurement at 60 (±10) minutes, the study eye was measured again at 120(±10) minutes post-injection. If there was no safety concerns at therepeat measurement, the patient was permitted to leave the clinic. Ifthe IOP remains elevated by ≥10 mm Hg from the pre-injectionmeasurement, and was of concern to the investigator following the repeatmeasurement, the patient remained in the clinic and was treated inaccordance with the investigator's clinical judgment prior to thepatient's discharge. An adverse event eCRF page was completed.

Detailed ocular examinations, including indirect ophthalmoscopy andslit-lamp examination, was performed throughout the study. Routinehematology, serum chemistry, coagulation, and urinalysis profiles, aswell as blood samples for serum study drug concentrations, CH50 and AH50assays, and antibodies to lampalizumab, were obtained from all patients.Aqueous humor paracentesis samples were also obtained from the patientswho consent to this procedure and sample collection.

With the exception of patients that continue into the OLE study at theMonth 18 visit, patients withdrawn from the study prior to completion(Month 19 visit for every-other-month treatment arms and Month 20 visitfor monthly treatment arms) were asked to return for early terminationvisit assessments after 30 (±7) days following the last study treatmentvisit. The visit included assessment of all adverse events (serious andnonserious; ocular and non-ocular).

3. Materials and Methods

3.1 Patient Selection and Sex Distribution

Written informed consent was obtained prior to initiation of any studyprocedures. Screening evaluation was performed any time within 14 dayspreceding Day 0 (the day of the first study treatment). Patientselection criteria were identical for the safety run-in phase andrandomization phase, with the exception of ocular inclusion criteria;patients with less severe visual impairment were enrolled in therandomized phase.

Enrollment of both men and women were allowed, provided the entrycriteria were met. However, pregnancy or breastfeeding were listed asexclusion criteria, thus women who were pregnant or breastfeeding wereexcluded from the trial.

The remaining inclusion/exclusion criteria applied to both male andfemale patients and pertain to issues of patient health performance andsafety issues.

Randomization was not made on the basis of sex, so the enrollment ofpatients was expected to reflect the demographics of the disease understudy.

3.1.1.b.1

3.1.1 Inclusion Criteria

Patients must meet the following criteria to be eligible for studyentry:

a. General Inclusion Criteria

1. Willingness and ability to provide signed Informed Consent and complywith study procedures as defined in the protocol.

2. Age 60-89 years

3. For sexually active women of childbearing potential, agreement to theuse of an appropriate form of contraception (or abstinence) for theduration of the study. A woman was considered not to be of childbearingpotential if she was postmenopausal or had undergone hysterectomy and/orbilateral oophorectomy. Sexually active men were required to use acontraceptive method (condom) to ensure that pregnancy was avoided intheir female partners unless a successful vasectomy (surgical malesterilization) had been performed

4. Ability and willingness to undertake all scheduled visits andassessments

b. Ocular Inclusion Criteria for the Study Eye

One eye was designated as the study eye. If both eyes were eligible, theeye with the worse VA and/or least function was selected for studytreatment (study eye).

-   -   1. Visual acuity        -   (a) For the safety run-in phase: BCVA of 20/125 to 20/400            inclusive (Snellen equivalent) using ETDRS charts        -   (b) For the randomized phase: BCVA of 20/50 to 20/400            inclusive (Snellen equivalent) using ETDRS charts    -   2. Well-demarcated area of GA secondary to AMD in the absence of        choroidal neovascularization (CNV)    -   3. GA was ≥1 disc area (DA) (2.5 mm²)    -   4. If GA was multifocal, at least one focal lesion was ≥0.5 DA        (1.25 mm²)    -   5. The total lesion size was ≤7 DA (17.5 mm²) and resided        completely within the FAF imaging field    -   6. Presence of hyperautofluorescence adjacent to the area of GA        (e.g., banded or diffuse junctional FAF patterns; Holz et al.,        Am J Ophthalmol, 143:463-472 (2007))    -   7. Sufficiently clear ocular media, adequate pupillary dilation,        and fixation to permit quality fundus imaging

c. Ocular Inclusion Criteria for the Non-Study Eye

-   -   1. GA secondary to AMD in the absence of CNV

3.1.2 Exclusion Criteria

Patients who met any of the following criteria were excluded from studyentry:

-   -   1. History of vitrectomy surgery, submacular surgery, or other        surgical intervention for AMD in the study eye    -   2. Previous subfoveal focal laser photocoagulation in the study        eye    -   3. Laser photocoagulation (juxtafoveal or extrafoveal) in the        study eye    -   4. Prior treatment with Visudyne®, external-beam radiation        therapy, or transpupillary thermotherapy in the study eye    -   5. Previous treatment with fenretinide or participation in        fenretinide studies    -   6. Previous treatment with eculizumab or participation in        eculizumab studies    -   7. Previous ITV drug delivery (e.g., ITV corticosteroid        injection, anti-angiogenic drugs, anti-complement agents, or        device implantation) in the study eye with the exception of the        patients previously treated ITV with lampalizumab. A single        intraoperative administration of an anti-VEGF agent during        cataract surgery for cystoid macular edema prophylaxis at least        3 months prior to screening is permitted.

a. GA Characteristics

-   -   1. GA in the study eye that extends beyond FAF imaging field or        fails to meet single or multifocal lesion criteria    -   2. Absence or minimal hyperautofluorescence adjacent to GA in        the study eye (e.g., focal FAF pattern; Holz et al. 2007)    -   3. GA in either eye due to causes other than AMD (e.g.,        Stargardt disease, pattern dystophies, cone-rod dystrophy, or        chloroquine/hydroxychloroquine toxicity)

b. Concurrent Ocular Conditions

-   -   1. RPE tear involving the macula in the study eye    -   2. History of retinal tear in the study eye    -   3. Any concurrent ocular or intraocular condition in the study        eye (e.g., cataract or epiretinal membrane) that, in the opinion        of the investigator, could either:        -   (a) Require medical or surgical intervention during the            study period to prevent or treat vision loss that might            result from that condition; or        -   (b) If allowed to progress untreated, could likely            contribute to loss of at least 2 Snellen equivalent lines of            BCVA during the study period.    -   4. History of other ocular or intraocular conditions that        contraindicate the use of an investigational drug or may affect        interpretation of the study results or may render the patient at        high risk for treatment complications    -   5. Active uveitis and/or vitritis (grade trace or above) in        either eye (see the definitions of uveitis and vitritis and for        uveitis and vitritis grading scales)    -   6. Current vitreous hemorrhage in the study eye    -   7. History of retinal detachment or macular hole (Stage 3 or 4)        in the study eye    -   8. Aphakia or absence of the posterior capsule in the study eye        -   (a) Previous violation of the posterior capsule in the study            eye is also excluded unless it occurred as a result of            yttrium aluminum garnet (YAG) laser posterior capsulotomy in            association with prior posterior chamber intraocular lens            implantation    -   9. Spherical equivalent of the refractive error in the study eye        demonstrating more than 8 diopters of myopia    -   10. For patients who have undergone prior refractive or cataract        surgery in the study eye, the preoperative refractive error in        the study eye should not have exceeded 8 diopters of myopia    -   11. Intraocular surgery (including cataract surgery) in the        study eye within 3 months preceding Day 0    -   12. Uncontrolled glaucoma in the study eye (defined as IOP ≥30        mmHg despite treatment with anti-glaucoma medication)    -   13. History of glaucoma-filtering surgery in the study eye    -   14. History of corneal transplant in the study eye    -   15. Diabetic retinopathy in either eye    -   16. Active or history of wet AMD in either eye    -   17. History of idiopathic or autoimmune-associated uveitis in        either eye    -   18. Active infectious conjunctivitis, keratitis, scleritis, or        endophthalmitis in either eye    -   19. History of infectious or inflammatory ocular disease in        either eye

c. Concurrent Systemic Conditions

-   -   1. Uncontrolled blood pressure (defined as systolic >180 mmHg        and/or diastolic>110 mmHg while patient is sitting)        -   (a) If a patient's initial measurement exceeded these            values, a second reading may be taken 30 or more minutes            later. If the patient's blood pressure must be controlled by            antihypertensive medication, the patient was eligible if            medication is taken continuously for at least 30 days prior            to Day 0.    -   2. Medical conditions that may be associated with a clinically        significant risk for bleeding    -   3. History of other disease, metabolic dysfunction, physical        examination finding, or clinical laboratory finding giving        reasonable suspicion of a disease or condition that        contraindicates the use an investigational drug or that might        affect interpretation of the results of the study or that        renders the patient at high risk for treatment complications    -   4. Treatment for active systemic infection    -   5. Predisposition or history of increased risk for infection    -   6. Known deficiency of complement factor D or alternative        complement pathway activity    -   7. Active malignancy or history of malignancy within the past 5        years (except completely resolved cutaneous basal cell        carcinoma)    -   8. History of allergy to fluorescein, not amenable to treatment    -   9. Inability to obtain FP, FAF, FA, SD-OCT, or NI images of        sufficient quality to be analyzed and graded by the central        reading center    -   10. Inability to comply with study or follow-up procedures    -   11. Previous participation in any studies of investigational        drugs within 3 months preceding Day 0 (excluding vitamins and        minerals)    -   12. Requirement for continuous use of any medications/treatments        indicated in the “Excluded Therapy” section (see Section 3.4.2)

3.3 Study Treatment

3.3.1 Trial Drug

Formulation

Lampalizumab drug product was provided as a sterile, white to off-white,lyophilized powder in a 6-cc USP/Ph. Eur. Type 1 glass vial intended forITV administration. Each glass vial contained nominal 40 mg oflampalizumab. Reconstitution of the drug product with sterile water forinjection (SWFI), USP/Ph. Eur., was required. After reconstitution, thedrug product was formulated as 100 mg/mL lampalizumab in 40 mML-histidine hydrochloride, 20 mM sodium chloride, 180 mM sucrose, 0.04%(w/v) polysorbate 20, pH 5.5. The drug product contained nopreservatives and was suitable for single use only.

Dosage, Administration and Storage

Dosing for Safety Run-In Phase: An open-label, 10-mg dose oflampalizumab was administered monthly to all safety run-in patients. Thestudy-drug treatment visits was scheduled every 30 (±7) days relative tothe date of the first injection (Day 0) until the tenth evaluablepatient completed the Day 90 (±7) visit following the third study drugtreatment, when a dosing hiatus ensued lasting approximately 7 days.During the hiatus, the safety of multiple dosing was reviewed. As thesafety run-in assessment demonstrated acceptable multidose safety andtolerability with lampalizumab as delineated in the DLC (see Section3.1.2), the randomized phase was initiated.

Following the hiatus, safety run-in patients continued monthly studydrug administration at the same dose as the patients in the randomizedphase for the remainder of their 18-month treatment period, followingthe same visit frequency and assessments as the randomized phase monthlydosing arm. These patients received a maximum of 18 lampalizumabtreatments during the study. Dosing was not repeated earlier than 22days after the previous dosing. Missed doses were not made up.

Dosing for Randomized Phase: As determined in the safety run-inassessment, the dose of lampalizumab was administered monthly or everyother month to patients in the study drug arms starting at the Day 0visit for a total of 18 injections in the monthly treatment arm and 9injections in the every-other-month treatment arm.

The sham injections were administered monthly or every other month topatients in the sham arms starting at the Day 0 visit for a total of 18injections in the monthly treatment arm and 9 injections in theevery-other-month treatment arm. Dosing was not repeated earlier than 22days after the previous dosing. Missed treatments were not made up.

Administration: Lampalizumab was reconstituted with Sterile Water ForInjection SWFI preparation of the dose. Vials of lampalizumab were forsingle-use only. Vials used for one patient were not used for any otherpatient.

Prior to the injection, patients were required to verify that they hadself-administered their antimicrobials 4 times daily for 3 days and wereinstructed to self-administer their antimicrobials again 4 times dailyfor 3 days post-injection. Prior to the Month 18 visit, patientselecting to continue into the OLE study were asked to sign the OLE studyInformed Consent Form and take protocol-specified antimicrobials asinstructed. For these patients, eligibility for enrollment into the OLEstudy were determined at their Month 18 visit. Patients who did notqualify or chose not to continue into the OLE study continued in thestudy for safety follow-up and have a final safety visit at the Month 19visit (the every-other-month treatment arms) or the Month 20 visit(monthly treatment arms).

Storage: Upon receipt of lampalizumab, vials were refrigerated at 2°C.-8° C. (36° F.-46° F.) until use. Lampalizumab vials were not usedbeyond the expiration date provided by manufacturer. No preservative wasused in lampalizumab drug product; therefore, the vial was intended forsingle use only. Vial contents were not frozen or shaken and wereprotected from direct sunlight. Within 2 hours following dosepreparation (reconstituted), lampalizumab was administered; the prepareddose may be maintained at room temperature prior to administration.

3.4 Other Treatments

3.4.1 Concomitant Therapy

Concomitant medications were any prescription drugs or over-the-counterpreparations other than protocol-specified procedural medications (e.g.,dilating drops or fluorescein dyes) and pre- and post-injectionmedications (e.g., proparacaine or antimicrobials) used by a patientwithin 7 days preceding Day 0 and through the conclusion of thepatient's study participation or early termination visit.

Patients who used other maintenance therapies continued their use.Patients required to use medications that were excluded were not beeligible for enrollment in the study. All concomitant medications werereported to the investigator and recorded on the appropriate eCRF.

The onset of glaucoma in the study eye during a patient's studyparticipation was treated as clinically indicated.

A patient with onset of mild non-proliferative diabetic retinopathy ineither eye during the study participation (e.g., an occasionalhemorrhage or microaneurysm) was permitted to continue on studytreatment after consultation with the Medical Monitor.

The onset of cataract or posterior capsular opacification in either eyeduring the patient's study participation was treated as clinicallyindicated. Dose-holding criteria was applied with cataract surgery orYAG laser treatment.

Laser photocoagulation treatment of new onset CNV in either eye duringthe patient's study participation was permitted provided the CNV wassufficiently distant to the GA lesion as determined by the readingcenter, could be resolved with a single laser treatment, and had beenapproved by the Medical Monitor. Dose-holding criteria was applied withlaser photocoagulation treatment.

3.4.2 Excluded Therapy

At the discretion of the investigator, patients were allowed to continueto receive medications and standard treatments administered for otherconditions. However, the following medications/treatments wereprohibited from use during the patient's participation in the study:

-   -   1. Systemic anti-VEGF agents    -   2. ITV anti-VEGF agents in either eye    -   3. ITV, subtenon, or topical (ocular) corticosteroids in either        eye (short-term use of topical corticosteroids is permitted        after cataract surgery)    -   4. Oral corticosteroids (prednisone or equivalent) at doses>10        mg/day    -   5. Intra-articular or intra-muscular corticosteroids may be used        in a limited fashion after consultation with the Medical Monitor    -   6. Intravenous corticosteroids    -   7. Systemic or IV immunomodulatory therapy (e.g., azathioprine,        methotrexate, mycophenolate mofetil, cyclosporine,        cyclophosphamide, anti-TNFs, eculizumab)    -   8. Treatment with Visudyne® in either eye    -   Other experimental therapies (except those with vitamins and        minerals)

3.5 Study Assessments

3.5.1 Definitions of Study Assessments

Study assessments are detailed below and were undertaken at variousstudy visits.

The patients enrolled in the safety run-in phase had approximately 29visits and patients enrolled to randomized phase had up to 22 studyvisits (excluding screening visit) during the study. With the exceptionof patients that continued into the OLE study at Month 18, any patientthat discontinued the factor D study prematurely (prior to the Month 19visit for every other month treatment arms and Month 20 visit formonthly treatment arms) had an early termination (ET) visit completed 30days (±7) after their last study treatment.

Study treatment visits were scheduled every 30 (±7) days relative to Day0 visit.

Routine hematology, serum chemistry, coagulation, urinalysis, andcomplement assessment (CH50 and AH50) was evaluated by the centrallaboratory. Other specimen evaluations were performed at Genentech (PK,anti-lampalizumab antibody, aqueous humor, and genotyping).

a. Patient Reported Outcomes

The NEI VFQ-25 questionnaire was administered by site personnel (otherthan the VA examiner), before the patient completed any other studyprocedures for that visit.

The FRII questionnaire was administered (for patients who are enrolledto the randomized phase and who read English) by site personnel (otherthan the VA examiner), before the patient completed any other studyprocedures for that visit.

b. Ocular Assessments

BCVA on ETDRS chart at a starting distance of 4 meters (performed priorto dilating eyes)

Contrast sensitivity measured by the number of letters read correctly onthe Pelli-Robson chart; performed prior to dilating eyes

SST Reading Speed assessment; performed prior to dilating eyes forpatients who read English)

MNRead binocular reading speed assessment (for patients who wereenrolled to the randomized phase and who read English; performedpre-injection prior to dilating eyes)

IOP measurement (performed prior to dilating eyes; the method used for apatient remained consistent throughout the study)

Slit-lamp examination (for grading scales for cells)

Dilated binocular indirect high-magnification ophthalmoscopy

Finger-counting test, or hand motion, or light perception testsperformed within 15 minutes post-injection for the study eye only byphysician

IOP measurement pre-injection both eyes and 60 (±10) minutespost-injection for the study eye only; if IOP increased 10 mmHg frompre-injection, then measured again at 120 (±10) minutes post-injection;the method used for a patient remained consistent throughout the study.

c. Ocular Imaging

The central reading center provided sites with a study manual andtraining materials for specified study ocular images. Before any studyimages were obtained, site personnel, test images, systems and software(where applicable) were certified/validated by the reading center asspecified in the study manual. All ocular images were obtained bytrained site personnel at the study sites and forwarded to the centralreading center for independent analysis and/or storage.

Ocular images obtained included the following:

-   -   Stereoscopic, digital color fundus photographs of both eyes    -   Fluorescein angiograms of both eyes (perform after laboratory        samples are obtained    -   FAF, NI, and SD-OCT images of both eyes

Additional details on obtaining these images were included in thecentral reading centermanual.

d. Laboratory Assessments

At the scheduled visit, specimens were collected prior to study eyetreatment and FA assessments (if applicable). Fasting was not requiredprior to specimen collection. All specimens were forwarded to thecentral laboratory for processing. The central laboratory eitherperformed the analysis or forwarded to Genentech for analysis.Instructions for obtaining, processing, storing, and shipping of allspecimens was provided in the Laboratory Manual. Lab supply kits wasprovided to the sites by the central laboratory.

The following assessments were performed:

-   -   1. Hematology: hemoglobin, hematocrit, quantitative platelet        count, red blood cells (RBC), white blood cells (WBC), and        differentials including neutrophils, bands, lymphocytes,        basophils, eosinophils, and monocytes (absolute and percent)    -   2. Serum chemistry: sodium, potassium, chloride, bicarbonate,        glucose, blood urea nitrogen (BUN), creatinine, calcium,        phosphorus, total and direct bilirubin, total protein, albumin,        AST, ALT, lactic dehydrogenase (LDH), alkaline phosphatase, and        uric acid    -   3. Urinalysis: specific gravity, pH, blood, protein, ketones,        glucose, bilirubin, urobilinogen, microscopic examination (if        any of the preceding urinalysis tests, other that glucose and        ketones, are abnormal)    -   4. Coagulation: aPTT and PTS.    -   5. Serum pregnancy test (β-human chorionic gonadotropin): for        women of child-bearing potential, including those who have had        tubal ligation. If positive, study drug will not be        administered.    -   6. Complement assessment: AH50 and CH50    -   7. PK assays:        -   (a) Serum samples were obtained to measure lampalizumab            concentration        -   (b) Serum samples were obtained for measurement of            anti-lampalizumab antibodies        -   (c) Anterior chamber (aqueous humor) paracentesis samples            was collected to assess PK and PD relationships

e. Clinical Genotyping Samples

A single whole-blood sample was collected from patients for geneticmarker analysis during the study. Collection of this sample was requiredfor all patients enrolled in the randomized phase of the study andresiding in the United States, with the exception of study centerslocated in Alaska and Oregon, where prohibited by law, and at studycenters with policies in place that prohibit collection of samples forgenetic marker analysis. The genetic marker sample was used to evaluaterelationships between genetic polymorphisms associated with AMD,baseline disease characteristics, and response to administration oflampalizumab.

f. Assay Methods

Drug concentration was determined in serum using an ELISA method.Anti-therapeutic antibodies (ATA) was detected in serum using a bridgingELISA.

3.5.2 Safety Run-In Phase: Assessments During Treatment

When a patient satisfied all eligibility criteria at both the screeningand the Day 0 visit (the day of initial study drug administration),including the receipt and evaluation of select images (FAF, NI, FP, FA,and SD-OCT obtained at screening visit) at the central reading center,the patient was assigned an identification number (a number differentfrom the patient's screening number) and drug kit on Day 0 by IWRS.Patient drug kit assignment occurred following pretreatment assessmentsand prior to study treatment administration on Day 0.

a. Day 0

Day 0 was the day of the first injection of lampalizumab. The followingassessments was performed on Day 0:

-   -   1. NEI VFQ-25 questionnaire; was administered by site personnel        (other than VA examiner), prior to the patient completing any        other study procedures)    -   2. Vital signs (blood pressure, respiration, pulse, and        temperature; perform pre-injection)    -   3. Ocular assessments        -   (i) BCVA testing at a starting distance of 4 meters (perform            pre-injection prior to dilating eyes)        -   (ii) Contrast sensitivity measured by the number of letters            read correctly on the Pelli-Robson chart (perform            pre-injection prior to dilating eyes)        -   (iii) SST Reading Speed assessment (perform pre-injection            prior to dilating eyes)        -   (iv) IOP measurement (obtain pre-injection for both eyes            prior to dilation; the method used for a patient must remain            consistent throughout the study)        -   (v) Slit-lamp examination (perform pre-injection)        -   (vi) Dilated binocular indirect high-magnification            ophthalmoscopy (perform pre-injection)    -   4. Review of the inclusion and exclusion criteria    -   5. Contact IWRS for patient's identification number and study        drug kit assignment prior to the initiation of treatment    -   6. Reconstitution of study drug (see the Pharmacy Binder)    -   7. Administration of lampalizumab injection in the study eye        -   (a) Prior to the injection, ensure that patients have            self-administered their antimicrobials 4 times daily for 3            days and instruct them to self-administer their            antimicrobials again 4 times daily for 3 days post-injection    -   8. Post-injection ocular assessments        -   (a) Finger-counting test, followed by hand-motion or            light-perception tests (when necessary) performed by the            physician within 15 minutes post-injection for the study eye            only        -   (b) IOP measurement 60 (±10) minutes post-injection for the            study eye only; the method used for a patient must remain            consistent throughout the study    -   9. Clinical evaluations        -   (a) Monitoring and recording of all adverse events        -   (b) Recording of concomitant medications used by the patient            within 7 days preceding Day 0        -   (c) Recording of concurrent ocular procedures

b. Day 1 and Day 7 Safety Assessment Visits

Safety run-in patients were seen in clinic for a safety evaluation onDay 1 (±0) and Day 7 (±2) following each study drug treatment until thestart of the hiatus. The following assessments were performed:

-   -   1. Clinical evaluations        -   (a) Vital signs (blood pressure, respiration, pulse, and            temperature)        -   (b) Recording of concomitant medications        -   (c) Recording of concurrent ocular procedures        -   (d) Monitoring and recording of all adverse events    -   2. Ocular assessments        -   (a) BCVA testing at a starting test distance of 4 meters            (perform prior to dilating eyes). Note: perform finger            counting test, followed by hand motion and light perception            tests, if necessary.        -   (b) IOP measurement (obtain for both eyes; the method used            for a patient must remain consistent throughout the study)        -   (c) Slit-lamp examination (perform pre-injection)        -   (d) Dilated binocular indirect high-magnification            ophthalmoscopy (perform pre-injection)    -   3. Serum sample for measurement of lampalizumab concentration        collection at Day 1 and Day 7 visits after the first study drug        treatment only    -   4. Whole blood sample for genetic marker analysis at Day 1 visit        after the first study drug treatment only

c. Safety Month X

Safety run-in patients had study drug treatment visits scheduled every30 (±7) days relative to Day 0 until the start of the hiatus. Thefollowing assessments were performed:

-   -   1. Vital signs (blood pressure, respiration, pulse, and        temperature)    -   2. Ocular assessments        -   (a) BCVA testing at a starting distance of 4 meters (perform            prior to dilating eyes)        -   (b) IOP measurement (obtain for both eyes prior to dilation;            the method used for a patient must remain consistent            throughout the study)        -   (c) Slit-lamp examination Dilated binocular indirect            high-magnification ophthalmoscopy    -   3. Ocular Imaging        -   (a) SD-OCT for both eyes    -   4. Contact IWRS for study drug kit assignment prior to the        initiation of treatment    -   5. Reconstitution of study drug (see Pharmacy Binder)    -   6. Administration of lampalizumab injection in the study eye        -   (a) Prior to the injection, ensure that patients have            self-administered their antimicrobials 4 times daily for 3            days and instruct them to self-administer their            antimicrobials again 4 times daily for 3 days post-injection    -   7. Post-injection ocular assessments        -   (a) Finger-counting test, followed by hand-motion or            light-perception tests (if applicable) performed by the            physician within 15 minutes post-injection for the study eye            only        -   (b) IOP measurement 60 (±10) minutes post-injection for the            study eye only; (the method used for a patient must remain            consistent throughout the study)    -   8. Clinical evaluations        -   (a) Monitoring and recording of all adverse events        -   (b) Recording of concomitant medications        -   (c) Recording of concurrent ocular procedures    -   9. Laboratory sample collection to be collected at each study        treatment visit until the start of the hiatus:        -   (a) Serum samples will be obtained to measure lampalizumab            concentration        -   (b) Serum samples will be obtained for measurement of            anti-lampalizumab antibodies        -   (c) Complement AH50 and CH50        -   (d) Hematology        -   (e) Serum chemistry        -   (f) Coagulation: aPTT and PT        -   (g) Urinalysis

3.5.3 Randomized Phase: Assessments During Treatment

When a patient satisfied all eligibility criteria at both the screeningand the Day 0 visit (the first day when study drug is administered),including the receipt and evaluation of select images (FAF, NI, FP, FA,and SD-OCT obtained at screening visit) at the central reading center,the patient was assigned an identification number (a number differentfrom the patient's screening number) and drug kit on Day 0 by IWRS.Patient drug kit assignment occurred following pretreatment assessmentsand prior to study treatment administration on Day 0.

a. Day 0

Day 0 was the day of the first study treatment injection. The followingassessments was performed on Day 0:

-   -   1. NEI VFQ-25 questionnaire; was administered by site personnel        (other than VA examiner), prior to the patient completing any        other study procedures) The FRII questionnaire was administered        (for patients who were enrolled to the randomized phase and who        read English) by site personnel (other than the VA examiner),        before the patient completed any other study procedures for that        visit.    -   2. Vital signs (blood pressure, respiration, pulse, and        temperature; perform pre-inj ection)    -   3. Ocular assessments        -   (a) BCVA testing at a starting distance of 4 meters (perform            pre-injection prior to dilating eyes)        -   (b) Contrast sensitivity measured by the number of letters            read correctly on the Pelli-Robson chart (perform            pre-injection prior to dilating eyes        -   (c) SST Reading Speed assessment (perform pre-injection            prior to dilating eyes)        -   (d) MNRead binocular reading speed assessment (for patients            who are enrolled to the randomized phase and who read            English); perform pre-injection prior to dilating eyes)        -   (e) IOP measurement (obtain pre-inj ection for both eyes            prior to dilation; the method used for a patient must remain            consistent throughout the study)        -   (f) Slit-lamp examination (perform pre-injection)        -   (g) Dilated binocular indirect high-magnification            ophthalmoscopy (perform pre-injection)    -   4. Review of the inclusion and exclusion criteria    -   5. Contact IWRS for patient's randomization identification        number and study treatment kit assignment prior to the        initiation of treatment    -   6. Reconstitution of study drug if applicable    -   7. Administration of study treatment injection (drug or sham as        per randomization) in the study eye        -   (a) Prior to the injection, ensure that patients have            self-administered their antimicrobials as prescribed and            instruct them to self-administer their antimicrobials again            4 times daily for 3 days post-injection    -   8. Post-injection ocular assessments        -   (a) Finger-counting test, followed by hand-motion or            light-perception tests (when necessary) performed by the            physician within 15 minutes post-injection for the study eye            only        -   (b) IOP measurement 60 (±10) minutes post-injection for the            study eye only; the method used for a patient must remain            consistent throughout the study    -   9. Clinical evaluations        -   (a) Monitoring and recording of all adverse events        -   (b) Recording of concomitant medications used by the patient            within 7 days preceding Day 0        -   (c) Recording of concurrent ocular procedures

b. Day 7 Visit

-   -   1. Clinical Evaluations        -   (a) Vital signs (blood pressure, temperature, respiration,            and pulse)        -   (b) Recording of concomitant medications        -   (c) Recording of concurrent ocular procedures        -   (d) Monitoring of concurrent ocular procedures    -   2. Ocular Assessments        -   (a) BCVA on ETDRS chart at a starting distance of 4 meters            (perform prior to dilating eyes)        -   (b) IOP measurement (perform prior to dilating eyes; the            method used for a patient must remain consistent throughout            the study)        -   (c) Slit-lamp examination        -   (d) Dilated binocular indirect high-magnification            ophthalmoscopy    -   3. Sample Collection        -   (a) Serum PK sample for lampalizumab concentration

c. Month 1 through Month 18 Visits

Month 18 was the final study visit for patients who qualified and choseto continue into the OLE study. Prior to the Month 18 visit, thesepatients were asked to sign the OLE Informed Consent Form and wereinstructed to take the protocol-specified antimicrobials. Eligibilityfor enrollment into the OLE study was determined at the Month 18 visit.

-   -   1. NEI VFQ-25 questionnaire at the Month 6, 12, and 18 visits        was administered by site personnel (other than VA examiner),        prior to the patient completing any other study procedures)    -   2. The FRII questionnaire at the Month 6, 12, and 18 visits was        administered (for patients who are enrolled to the randomized        phase and who read English) by site personnel (other than the VA        examiner), before the patient completed any other study        procedures for that visit.    -   3. Vital signs (blood pressure, respiration, pulse, and        temperature; perform pre-injection)    -   4. Physical exam at the Month 12 and 18 visits    -   5. Ocular assessments        -   (a) BCVA testing at a starting distance of 4 meters (perform            pre-inj ection prior to dilating eyes)        -   (b) Contrast sensitivity at Month 6, 12, and 18 visits            measured by the number of letters read correctly on the            Pelli-Robson chart (perform pre-injection prior to dilating            eyes)        -   (c) SST Reading Speed assessment at Months 6, 12, and 18            visits (perform pre-injection prior to dilating eyes)        -   (d) MNRead binocular reading speed assessment (for patients            are enrolled to the randomized phase and who read English)            at the visits at Months 6, 12, and 18 (perform pre-injection            prior to dilating eyes)        -   (e) IOP measurement (obtain pre-injection for both eyes            prior to dilation; the method used for a patient must remain            consistent throughout the study)        -   (f) Slit-lamp examination (perform pre-injection        -   (g) Dilated binocular indirect high-magnification            ophthalmoscopy (perform pre-inj ection)    -   6. Ocular imaging (forward images to the central reading center        -   (a) FAF and NI for both eyes at Month 6, 12, and 18 visits        -   (b) Fundus photographs of both eyes at Month 6, 12, and 18            visits        -   (c) SD-OCT images of both eyes starting at Month 1 and            continuing monthly through the Month 12 visit; subsequently,            the images will be taken at the Month 15 and 18 visits only        -   (d) Fluorescein angiography at Month 6, 12, and 18 visits    -   7. Study treatment administration:        -   (a) Monthly treatment arms: visits Month 1 through Month 17        -   (b) Every-other-month treatment arms: visits Month 2, 4, 6,            8, 10, 12, 14, and 16        -   (c) Contact IWRS for patient's study treatment kit            assignment (if applicable) prior to the initiation of            treatment        -   (d) Reconstitution of study drug (see Pharmacy Binder for            details)    -   8. Administration of study treatment injection (drug or sham as        per randomization) in the study eye        -   (a) Prior to the injection, ensure that patients have            self-administered their antimicrobials as prescribed and            instruct them to self-administer their antimicrobials again            4 times daily for 3 days post-injection. Prior to the Month            18 visit, patients electing to continue into the OLE study            were asked to sign the OLE study Informed Consent Form and            take protocol-specified antimicrobials as instructed.    -   9. Post-injection ocular assessments        -   (a) Finger-counting test, followed by hand-motion or            light-perception tests (when necessary) performed by the            physician within 15 minutes post-injection for the study eye            only        -   (b) IOP measurement 60 (±10) minutes post-injection for the            study eye only; the method used for a patient must remain            consistent throughout the study    -   10. Clinical evaluations        -   (a) Monitoring and recording of all adverse events        -   (b) Recording of concomitant medications        -   (c) Recording of concurrent ocular procedures    -   11. Central laboratory assessments        -   (a) The central laboratory assessments are to be performed            prior to the FA assessment; patients do not need to fast            prior to collecting the specimen.        -   (b) Hematology, serum chemistry, coagulation: aPTT and PT,            serum chemistry, urinalysis at Month 6, Month 12, and Month            18 visits        -   (c) Serum pregnancy test at Month 12 and Month 18 visits        -   (d) Serum lampalizumab concentration at visits Month 1, 2,            3, 6, 9, 12, 15, and 18        -   (e) Serum anti-lampalizumab antibody visits at Month 1, 2,            3, 6, 9, 12, 15, and 18        -   (f) Complement assessment: AH50 and CH50 at Month 3, 6, 9,            12, 15, and 18        -   (g) Collect a whole blood sample for genetic markers at            Month 1 visit        -   (h) Anterior chamber (aqueous humor) paracentesis samples            will be collected sites at Day 0, Month 6, and Month 12            visits to assess PK and PD relationships    -   12. For a complete list of laboratory tests, refer to the        Laboratory Manual.    -   13. Subsequent to the initial treatment visit, patients treated        with study drug or sham received a telephone call 7 (±2) days        after each treatment visit to solicit adverse events.

d. Month 19 and Month 20 or Early Termination Visit

Month 19 (every-other-month treatment arms) and Month 20 (monthlytreatment arms) safety visits were conducted only for factor D studypatients who were not eligible or who chose not to continue into the OLEstudy.

The following assessments were performed at the Month 19, Month 20, andearly termination visits unless noted otherwise:

-   -   1. NEI VFQ-25 questionnaire only at the early termination visit;        was administered by site personnel (other than VA examiner),        prior to the patient completing any other study procedures)    -   2. The FRII questionnaire only at the early termination visit;        was administered (for patients who are enrolled to the        randomized phase and who read English) by site personnel (other        than the VA examiner), before the patient completed any other        study procedures for that visit.    -   3. Clinical evaluations        -   (a) Vital signs (blood pressure, respiration, pulse, and            temperature)        -   (b) Physical examination: perform only at the early            termination visit        -   (c) Monitoring and recording of all adverse events        -   (d) Recording of concomitant medications        -   (e) Recording of concurrent ocular procedures    -   4. Ocular assessments        -   (a) BCVA testing at a starting distance of 4 meters        -   (b) Contrast sensitivity only at the early termination            visit; it is measured by the number of letters read            correctly on the Pelli-Robson chart (perform prior to            dilating eyes)        -   (c) SST Reading Speed assessment at the early termination            visit only (perform prior to dilating eyes)        -   (d) MNRead binocular reading speed assessment (for patients            who were enrolled to the randomized phase and who read            English) at the early termination visit only (perform prior            to dilating eyes)        -   (e) IOP measurement; the method used for a patient remained            consistent throughout the study)        -   (f) Slit-lamp examination (for grading scales of            flare/cells)        -   (g) Dilated binocular indirect high-magnification            ophthalmoscopy    -   5. Central laboratory assessments were performed only at the        early termination visit        -   (a) The central laboratory assessments were performed prior            to the FA assessment; patients did need to fast prior to            collecting the specimen.        -   (b) Hematology        -   (c) Serum chemistry        -   (d) Coagulation: aPTT and PT        -   (e) Urinalysis        -   (f) Serum pregnancy test        -   (g) Serum lampalizumab concentration        -   (h) Serum anti-lampalizumab antibody        -   (i) Complement assessment: AH50 and CH50

3.5.4 Study Completion/Early Termination Visit

If a patient experienced eye pain, a decrease in vision, unusualredness, or any other new ocular symptoms in the study eye, theinvestigator determined whether the patient was to return to the clinicfor a safety assessment. If a visit was required, the assessments wereperformed.

3.6 Assay Methods

Drug concentration was determined in serum using an ELISA method. ATAswill be detected in serum using a bridging ELISA.

3.7 Statistical Methods

The database was cleaned and locked when all patients completed ordiscontinued the treatment and safety follow-up period. Only patientsand study personnel who were scoring visual acuity of patients weremasked to treatment assignment. Two analyses were planned during thestudy: 1) a primary analysis after all patients in the randomized phasecompleted the 18-month treatment period; and 2) a final analysis atMonth 20 performed for patients who did not participated in the OLEstudy and completed the factor D safety follow-up period.

The efficacy analysis was based on the modified intent-to-treatpopulation, which was defined as all randomized patients who receive atleast one dose of treatment and had at least one post-baseline primaryefficacy measurement. For the efficacy analysis, patients were groupedaccording to the treatment assigned at randomization.

The safety analysis was based on all patients who receive at least onedose of treatment. Patients were grouped according to treatmentreceived.

All statistical tests were two-sided with a type I error rate of 0.2. Tounderstand the clinical significance of the estimated treatment effectsand to aid in the interpretation of the formal hypothesis testing,two-sided 80% confidence intervals were provided.

Descriptive summaries included mean, standard deviation, median, andrange for continuous variables and counts and percentages forcategorical variables. All analyses, summaries, and listings wereperformed using SAS software (Version 9.1 or higher). Detailedstatistical methods were outlined in the Data Analysis Plan (DAP).

3.7.1 Analysis of Treatment Group Comparability

Demographic and baseline characteristics—such as age, sex, race, totallesion size, and baseline VA score—were summarized for all randomizedpatients by treatment group by use of descriptive statistics.

3.7.2 Efficacy Analysis

a. Primary Efficacy Endpoint

The primary efficacy endpoint was mean GA area growth rate from baselineat Month 18 as measured by FAF; the primary efficacy endpoint wasanalyzed at Month 18. Stratified ANOVA was used for the primary analysiswith baseline lesion size as the stratification variable. Confidenceintervals on treatment effect sizes was provided, along with descriptivesummary statistics for each treatment group.

b. Secondary Efficacy Endpoint

Similar analysis methods as for the primary endpoint was used for thefollowing secondary endpoints:

-   -   1. D Mean growth rate of GA area from baseline at 18 months by        digitized stereoscopic color fundus photographs    -   2. Mean change from baseline in BCVA at 18 months using the        ETDRS system

3.8 Pharmacokinetic and Pharmacodynamic Analyses

R Individual and mean serum lampalizumab concentration-time data wastabulated and plotted by dose level. The serum pharmacokinetics oflampalizumab was summarized by parameters estimates of exposure betweendose intervals (AUC), maximum observed serum concentration (C_(max)),and time to steady-state and accumulation ratio. Estimates for theseparameters was tabulated and summarized by descriptive statistics.Anterior chamber (aqueous humor) paracentesis samples were collected toassess PK and PD relationships. Additional PK, PD, and biomarkerinvestigations were conducted.

3.9 Handling of Missing Data

All efforts were made to minimize missing data. For the primary efficacyanalysis, all patients in the modified ITT population were included inthe analysis. If the primary efficacy measure at Month 18 was missing,data was imputed using the last observation prior to Month 18. If deemedappropriate, additional imputation methods were applied to furthercharacterize the results. The details of missing data handling methodswere specified in the DAP.

Example 2 Efficacy Analysis

Treatment effects at 18 months from patients who received lampalizumabadministered IVT versus or sham injection as described in Example 1 areset forth in FIGS. 3-7 below. FIGS. 3-7 set forth the treatment effectby measuring mean change from in GA area (mm2) from baseline at month18.

FIGS. 3A and 3B shows the preliminary efficacy results right after theprimary database lock for the MAHALO phase II study with an all-cornerspopulation. The study met its primary endpoint of mean change frombaseline in GA area at 18 months as measured by fundus autofluorescence(FAF) and met its secondary endpoint of mean change from baseline in GAarea at 18 months as assessed by color fundus photography (CFP) in thelampalizumab monthly group. A positive treatment effect in slowing theprogression of GA area growth was observed in the monthly groupbeginning at 6 months and extending through 18 months. On the basis ofthe unadjusted means with the LOCF data, the lampalizumab monthly armhad a 23.1% reduction in progression of GA area growth relative to thepooled sham arm (FIG. 3A). On the basis of the least squares means fromthe stratified analysis of variance (Henry Scheffe. Chapter 1.2“Mathematical Models” in The Analysis of Variance, New York: John Wiley& Sons, Inc., 1999, p. 4-7), stratified by lesion size categories atbaseline, <4 DA vs.>4 DA) with the LOCF data, the lampalizumab monthlyarm had a 20.4% reduction in the progression of GA area growth relativeto the pooled sham arm (FIG. 3B). The results demonstrated a clinicallymeaningful and statistically significant effect of lampalizumabadministered monthly on reducing GA area growth over the 18-monthstudy-treatment period. “Sham pooled” refers to the control treatmentgroups receiving sham monthly and sham every other month combined.“afD1m” refers to the treatment group receiving lampalizumab everymonth. “afD2m” refers to the treatment group receiving lampalizumabevery other month. LOCF method refers to thelast-observation-carried-forward method used for the imputation ofmissing data.

FIG. 7 summarizes the least squares mean of DDAF change from baseline inGA area by FAF in patients carrying the CFH, C2/CFB and CFI risk allelescompared to patients carrying the CFH and C2/CFB risk alleles withoutthe CFI risk allele in the sham and lampalizumab monthly treatmentgroups. The data in this figure are adjusted for lesion size at baselineas continuous variable and lesion size category at baseline (<4DAand >=4DA). The treatment effect and reduction rate are calculated atmonth 18, the primary efficacy time point. The absolute treatment effectat month 18 was 1.837 mm2 which corresponds to a reduction rate of 44%.In contrast, no treatment effect was observed in lampalizumab treatedpatients without the CFI risk allele. Moreover, patients with the CFIrisk allele showed a more rapid progression in the sham control groupversus the sham group without the CFI risk allele.

The above findings suggest the CFI biomarker is both prognostic for AMDprogression and predictive for treatment response to lampalizumab.

Example 3 Genotyping Analysis Results

Participants in the anti-factor D study (n=93) were genotyped using theIllumina Omni 2.5M SNP chip. For the genotyping, single whole bloodsamples were collected from each patient. Genomic DNA was extracted fromeach sample and analyzed using the Illumina Omni 2.5M SNP chip (Oliphantet al., Biotechniques, Suppl: 56-8, 60-1 (2002)). We applied thefollowing quality control measures to the genome-wide data, removing asfollows: samples with >5% missing SNPs (n=44,180), samples with >5%missing SNPs (n=0), SNPs with minor allele frequency <0.1 (n=831,590),Hardy-Weinberg Equilibrium <1e-8 (n=1,678), duplicated/related samples(n=0), SNPs that did not map to the proper chromosome (n=3,624), SNPswith no rs identifier (n=56,333). This left a total of 1,442,450 SNPsafter quality control measures.

From this set of 1,442,450 SNPs, we selected 4 index SNPs (rs10737680(CFH); rs429608 (C2/CFB); rs2230199 (C3); rs4698775 (CFI)) from themanuscript Fritsche et al. (Nature Genetics, 45(4): 435-441 (2013)) (orsurrogate SNPs (r²>0.8 if the index SNP identified in the manuscript wasnot in our dataset) associated with five genes (CFH, C2, CFB, C3 andCFI) associated with risk of age-related macular degeneration. SurrogateSNPs were rs1329428 (CFH) and rs17440077 (CFI)). C2 and CFB are locatedclose to each other on the chromosome and thus are both tagged by thers429608 SNP and the risk locus is referred to herein as the “C2/CFBrisk locus” that includes both the C2 and CFB genes. The C2/CFB locus,which is tagged by rs429608, is associated with risk of age-relatedmacular degeneration. As sample size in this study was limited, wegrouped individuals for each SNP as “risk allele carriers” (heterozygousor homozygous for the risk allele) or “non-risk allele carriers”(homozygous for the non-risk allele). For all SNPs (rs1329428,rs17440077, rs429608 and rs2230199), the risk allele was a guanine (G)in our dataset. “Index SNP” when used herein refers to the SNP with thestrongest p value within a particular region in a given study. Forexample, the index SNP for CFH, CFI, C2/CFB or C3 is the SNP with thestrongest p value within the Fritche Nature Genetics (Fritsche et al.,Nature Genetics, 45(4): 435-441 (2013)) study for the CFH, CFI, C2/CFBor C3 risk loci, respectively.

We compared the difference in the FAF measure of lesion size in mm² frombaseline to 18 months using the observed dataset.

The difference between anti-factor D monthly and sham (pooled) wascalculated as: mean DDAF pooled sham—DDAF in anti-factor D monthly/meanDDAF in the pooled sham.

We found that all individuals (except 2 in the sham group) in our studycarried the CFH risk allele (FIG. 4). All individuals (except 1 in thesham group) carried the C2/CFB risk allele (FIG. 4). As such, we werenot able to determine if carrying the risk allele for these two geneshad any effect on efficacy of anti-factor D. We saw no differencebetween risk allele and non-risk allele carriers for C3. For CFI, we sawpatients in the treatment group (n=16) with the CFI risk allele had a44% reduction at month 18 in lesion growth compared to patients in thesham group with the CFI risk allele (n=12) (FIG. 6; data was leastsquares mean). Patients in the treatment group without the CFI riskallele (n=8) had a negligible 9% progression (FIG. 5, bottom row) inlesion growth compared to patients in the sham group without the riskallele (n=17) (FIG. 5). Further, we saw patients in the treatment group(n=9) with the CFI risk allele and a baseline BCVA of 20/50-20/100 had54% reduction at month 18 in lesion growth compared to patients in thesham group with the CFI risk allele and a baseline BCVA of 20/50-20/100(n=6) (FIG. 8; data was least squares mean).

Since the rs4698775 SNP(CFI SNP) was not on the Illumina Omni 2.5M SNPchip, we also subsequently genotyped the same patients samples from theanti-Factor D study for the rs4698775 SNP (identified in the Fritsche etal. manuscript (Fritsche et al., Nature Genetics, 45(4): 435-441 (2013))directly using a Taqman assay. Results using SNP rs4698775 did notsignificantly differ from results using SNP rs17440077. Specifically,because of the linkage disequilibrium pattern between SNP rs17440077 andSNP rs4698775, both SNPs provided nearly identical genotype informationin the patient samples. Further, an effect on lesion growth comparableto that seen with the rs17440077 SNP (FIG. 6) was also observed with thers4698775 SNP.

This data suggests that the CFI risk allele may be useful in predictingresponsiveness to lampalizumab as patients with the CFI risk allele hada greater reduction in lesion growth compared to patients without theCFI risk allele. This data also suggests that the CFI risk allele may beuseful in the prognosis of AMD progression as patients with the CFI riskallele had worse prognosis (e.g. AMD progression) than patients who didnot carry the CFI risk allele. Alternate SNPs (for example those listedin Tables 4-7 for rs17440077) with LD with the selected CFI SNPs(rs4698775 and/or rs17440077) may also be useful in predictingresponsiveness to lampalizumab as patients and may be useful in theprognosis of AMD progression. Alternate SNPs with LD with the selectedCFH SNPs (rs10737680 and/or rs1329428), C2 or CFB SNPs (rs429608) and/orC3 SNP (rs2230199) may also be useful in predicting responsiveness tolampalizumab as patients and may be useful in the prognosis of AMDprogression.

Example 4 Adverse Events

The most common adverse event (AE) was conjunctival haemorrhage: 2.4% inthe sham group, 48.8% in the lampalizumab monthly group and 34.1% in thelampalizumab every other month group (see Table 8). The most commonanti-factor D-related adverse event (AE) was the increased intraocularpressure (IOP), occurring in 1 patient in the lampalizumab monthly group(1 out of 43 patients; 2.3% in the monthly group) and 3 patients inlampalizumab every other month group (3 out of 44 patients, 6.8%) (Table8 shows all AE regardless of whether it is drug-related or notdrug-related; see note in Table 8).

The proportion of patients who discontinued treatment due to ocularadverse events in the study eye was 7% and 2.3% for patients receivingthe anti-factor D antibody (monthly and every other month, respectively)and 2.4% for sham-injected treated patients. A summary of adverse eventsis shown in Table 3. There were no deaths, no ocular SAEs suspected tobe caused by study drug, and no ocular SAEs in study eye leading totreatment discontinuation. At this stage of development, the safetyprofile for lampalizumab remains acceptable.

TABLE 3 Overall Adverse Event Profile lampalizumab Sham lampalizumabEvery Other Pooled Monthly Month (n = 42) (n = 43) (n = 44) # (%) ofpatients with at least one event Ocular SAEs in study eye 1 3 (2.4%)(0.0%) (6.8%) Ocular SAEs in fellow eye 1 (0.0%) 2 (2.4%) (4.5%)Systemic (non-ocular) SAEs 15 11 10 (35.7%) (25.6%) (22.7%) Ocular AE inthe study (0.0%) 4 3 eye suspected (9.3%) (6.8%) to be caused by studydrug Ocular AE in study eye leading 1 3 1 to treatment discontinuation(2.4%) (7.0%) (2.3%) Non-ocular AE suspected to (0.0%) 1 1 be caused bystudy drug (2.3%) (2.3%) Non-ocular AE leading to 3 (0.0%) 4 treatmentdiscontinuation (7.1%) (9.1%)

TABLE 8 Ocular AEs in Study Eye (Occurring in ≥ 3 Patients in Any Group)lampa- lampa- lizumab Sham lizumab Every Pooled Monthly Other MonthMedDRA Preferred Term (n = 42) (n = 43) (n = 44) >-Any adverse events-24 (57.1%) 36 (83.7%) 30 (68.2%) AGE-RELATED MACULAR   (0.0%)  2 (4.7%) 3 (6.8%) DEGENERATION BLEPHARITIS  2 (4.8%)  1 (2.3%)  5 (11.4%)CATARACT  3 (7.1%)  2 (4.7%)  3 (6.8%) CONJUNCTIVAL  9 (21.4%) 21(48.8%) 15 (34.1%) HAEMORRHAGE CONJUNCTIVAL OEDEMA   (0.0%)  1 (2.3%)  3(6.8%) DRY EYE   (0.0%)  2 (4.7%)  3 (6.8%) EYE IRRITATION  1 (2.4%)  4(9.3%)  4 (9.1%) EYE PAIN  4 (9.5%) 10 (23.3%)  6 (13.6%) EYE PRURITUS 3 (7.1%)  1 (2.3%)  3 (6.8%) FOREIGN BODY  1 (2.4%)  4 (9.3%)  2 (4.5%)SENSATION IN EYES INTRAOCULAR   (0.0%)  6 (14.0%)  7 (15.9%) PRESSUREINCREASED * LACRIMATION INCREASED  1 (2.4%)  3 (7.0%)  4 (9.1%) OCULARHYPERAEMIA  2 (4.8%)  3 (7.0%)  5 (11.4%) PUNCTATE KERATITIS  1 (2.4%) 4 (9.3%)  2 (4.5%) RETINAL HAEMORRHAGE  3 (7.1%)  1 (2.3%)  3 (6.8%)VISION BLURRED  1 (2.4%)  2 (4.7%)  3 (6.8%) VITREOUS DETACHMENT  3(7.1%)  2 (4.7%)  4 (9.1%) VITREOUS FLOATERS  1 (2.4%)  3 (7.0%)  2(4.5%) * Note: 1 patient in the lampalizumab monthly group and 3patients in the lampalizumab every other month group were reported tohave increased intraocular pressure suspected to be related to the studydrug.

Example 5 eQTL Analysis

While SNP rs4698775 is located in an intron of gene CCDC109B, CFI is byfar the most compelling candidate gene at the locus based on genetic andbiologic evidence. We examined whether this rs4698775 SNP may be anexpression quantitative trait locus (eQTL) affecting levels of CFI mRNAin the liver,

To perform eQTL analysis, TCGA RNA-seq data was obtained from the CancerGenomics Hub at UC Santa Cruz (Cancer Genome Atlas (TCGA) database)(Cancer Genome Atlas Research Network, Nature, Comprehensive GenomicCharacterization Defines Human Gioblasoma Genes and Core Pathways,455(7216):1061-8 (Oct. 23, 2008); Collins et al., Sci. Am, Mapping theCancer Genome. Pinpointing the Genes Involved in Cancer Will Help Charta New Course Across the Complex Landscape of Human Malignancies, 296(3):50-7 (March 2007)). TCGA contains RNA-seq and genotype data for tumorand normal samples from multiple tissues in the body. For this study, weused 34 samples of normal liver tissue. RNAseq data for these wasanalyzed using HTSegGenie (Pau, G. B. et al., HTSeqGenie: a softwarepackage to analyse high-throughput sequencing experiments (2012)), asfollows: first, reads with low nucleotide qualities were removed (70% ofbases with quality <23). The reads that passed were then aligned to thereference genome GRCh37 (Genome Research Consortium 37) using GSNAP(Genomic Short-read Nucleotide Alignment Program) (Wu, T D. et al.,Bioinformatics, Fast and SNP-tolerant detection of complex variants andsplicing in short reads, 26(7):873-81 (Apr. 1, 2010). Alignments of thereads that were reported by GSNAP as “uniquely mapping” were used forsubsequent analysis. CH gene expression level for each sample was thenquantified in terms of RPKM=number of reads aligning to CFI gene/(totalnumber of uniquely mapped reads for the samples×CFI gene length).Genotype data for these samples was obtained through the database ofGenotypes and Phenotypes (dbGaP; dbGaP is a site hosted by NCBI toarchive and distribute results of studies that investigate theinteraction between genotype and phenotype) and included genotypes forthe Affymetrix 6.0 (1 million) SNP array. As the SNP of interest,rs4698775 was not directly assayed by this array, genotype imputationwas performed using a workflow that included pre-phasing using SHAPEIT(Delaneau, O., Nature Methods, Improved whole-chromosome phasing fordisease and population genetic studies, 10: 5-6 (2013)), followed byimputation using IMPUTE2 (Howie, B. N. et al., PLoS Genet, A Flexibleand Accurate Genotype Imputation Method for the Next Generation ofGenome-Wide Association Studies, 5(6):e1000529 (2009)) and referencehaplotypes from the 1000 Genomes project (1000 Genomes ProjectConsortium, Abecasis G R. et al., Nature, A map of human genomevariation from populationscale sequencing, 467(7319):1061-73 (2010)).Association analysis was then carried out which included performinglinear regression of log (CFI RPKM) on the rs4698775 genotype codedadditively (i.e. 0, 1, 2 copies of “T” allele).

The results showed that CFI expression is highest in liver tissue of thebody, the site of synthesis for CFI (FIG. 9). When grouping by genotypefor rs4698775, we saw a significant reduction in CH mRNA (p=0.02) innormal TCGA liver samples. In short, rs4698775 genotype wassignificantly associated with CFI mRNA levels normal TCGA liver samples(p=0.02). Risk allele homozygotes (GG) had less CFI mRNA thanheterozygotes (GT), who in turn had less CFI mRNA than non-risk allelehomozygotes (TT) (FIG. 10). These results were consistent with ourhypothesis in which CFI is a negative regulator of the alternativecomplement pathway and that Risk allele carriers have lower levels ofCFI available to regulate the alternative complement pathway. With theseresults, we showed a possible functional effect of the common GWASassociated SNP (rs4689775) used in our phase II MAHALO analysis.

Example 6 CFI Rare Variant Analysis

A recent report has shown a significant excess (p=1.7×10-8) of raremissense variation in the CH gene of AMD patients (7.8%) compared tocontrols (2.3%) (Seddon, et al. Nat. Genet. 2013 45:1366-70). A secondreport, mainly focusing on one particular rare variant within the CFIgene, G119R, showed that these types of variants have a large impact onAMD risk (p=3.79×10-6; OR 22.20) (van de Ven, et al. Nat. Genet. 201345:813-7).

Sanger dideoxy sequencing was used to re-sequence exons in the CH genefor all patients in the MAHALO study with available DNA. PolymeraseChain Reaction (PCR) amplification was performed using standard PCRtechniques using AmpliTaq Gold PCR Master Mix (Applied Biosystems) whichincludes all of the chemical components, except primers and template,necessary fbr amplification of samples via PCR and the AppliedBiosystems 3730/3730x1 DNA Analyzer which is an automated,high-throughput, capillary electrophoresis system used for analysingfluorescently labelled DNA fragments. A two step “boost/nest” PCRstrategy was used which involves the amplification of a large portion ofa genomic DNA template first to generate a boost product, and then usingthe boost product as a template, to amplify a smaller region that wasused for sequencing. Using the “boost/nest” strategy, we amplified largeregions of the CFI gene from genomic DNA from patients in the MAHALOstudy with “boost” primers to generate a product for use as a templatein a secondary nested reaction. “Nest” primers were used in thesecondary nested PCR reaction to amplify a smaller region. The productof the nested reaction was used as a template for sequencing usingstandard sequencing techniques.

We re-sequenced all exons of CFI in our MAHALO patients with availableDNA and found that 6 (6.9%) of them carried a rare missense variant(FIG. 11) We saw a significant enrichment of CFI rare missense variationin our MAHALO trial samples from patients with GA, compared to controls(p=0.015). These patients that carried the rare missense variant wereequally divided between our sham, every other month and monthly arms. Inthe sham group, both individuals (290E>D and 553P>S in the CFI gene)with rare variants were non-risk allele carriers for rs17440077(CFI-based on rs17440077). We observed that these rare variant positiveindividuals who are non-risk allele carriers for the rs17440077SNP(CFI-based on rs17440077) used in the MAHALO study have a lesion areagrowth differential from baseline to 18 months (e.g. GA progressionrates) similar to risk allele carriers (CFI+ based on rs17440077) (FIG.12).

Because the growth rate for these non-risk allele carriers with rarevariants is similar to those of risk allele carriers, GA patients whocarry these rare missense variants may progress at a rate similar torisk allele carriers, regardless of whether they are classified as riskallele carriers or non-risk allele carriers based on the commonrs17440077 SNP at CFI.

Example 7 Selection of Patients for Anti-Factor D Therapy

Patients diagnosed with GA were genotyped for the presence ofpolymorphisms associated with genes encoding selected complementfactors. Presence of identified risk alleles and combinations thereof isindicative of the patient's likelihood to respond to treatment withanti-Factor D, such as lampalizumab.

Specifically, genotypes of the patients were detected by TaqManreal-time PCR. Each reaction included 0.4 μM each of forward and reverseprimer and 0.15-0.3 μM detection probe (Table 9), uracil-N-glycosylase,0.04-0.32 mM dNTPs (including dUTP), DNA polymerase and a suitable DNApolymerase buffer (including aptamer). The reactions were subjected tothe following thermal cycling profile on the COBAS® 4800 instrument(Roche Molecular Diagnostics, Indianapolis, Ind.): 50° C. for 5 minutes,followed by 2 cycles of 95° C. (10 seconds) to 62° C. (30 seconds), and55 cycles of 93° C. (10 seconds) to 62° C. (30 seconds), followed by 37°C. (10 minutes) and 25° C. (10 minutes). Fluorescence data was collectedat the start of each 62° C. step.

TABLE 9  Oligonucleotides used in TaqMan RT-PCR SEQ ID NO: Name PurposeSequence SEQ ID NO: 17 CCDC-LP03 CFI FWD PrimerGCCTGCTAGCAACAAATTCACTCAL SEQ ID NO: 18 CCDC-LP02 CFI FWD PrimerCCTGCTAGCAACAAATTCACTCAL SEQ ID NO: 19 CCDC-RP05 CFI REV PrimerCACATACGTATATCATTTTCAAACTGCAGAL SEQ ID NO: 20 CCDC-RP02 CFI REV PrimerGTATATCATTTTCAAACTGCAGAAAATCAL SEQ ID NO: 21 CCDC-G03CFI Probe for G SNP FTCGGQAATGCTAAATATTTTATCCCACTTCTTP SEQ ID NO: 22CCDC-G01 CFI Probe for G SNP FTTCTCGGQAATGCTAAATATTTTATCCCACTPSEQ ID NO: 23 CCDC-T05 CFI Probe for T SNPHCTCTGAQATGCTAAATATTTTATCCCACTTCTP SEQ ID NO: 24 CCDC-T01CFI Probe for T SNP HTTCTCTGQAATGCTAAATATTTTATCCCACTP SEQ ID NO: 25SKIV2L_LP02 C2 FWD Primer TCGGTGAGAGATGGACACTCAATL SEQ ID NO: 26SKIV2L-LP03 C2 FWD Primer CGGTGAGAGATGGACACTCAATACL SEQ ID NO: 27SKIV2L_RP02 C2 REV Primer ACATCGTTGATATAGTGAACCTCATCL SEQ ID NO: 28SKIV2L-RP01 C2 REV Primer TCGTTGATATAGTGAACCTCATCL SEQ ID NO: 29SKIV2L_G11 C2 probe for G SNP FCTGSGGQAGTCAATCCTTGGCCTCTTP SEQ ID NO: 30SKIV2L-G12 C2 probe for G SNP FCTGGSGQAGTCAATCCTTGGCCTCTTP SEQ ID NO: 31SKIV2L_G13 C2 probe for G SNP FCTGGSGQAGTCAATCCTTGGCCTCTTP SEQ ID NO: 32SKIV2L_A01 C2 probe for A SNP HACTGGAGQAGTCAATCCTTGGCCTCTP SEQ ID NO: 33SKIV2L-A03 C2 probe for A SNP HACTGGAQGAGTCAATCCTTGGCCTCTP SEQ ID NO: 34CFH-LP01 CFH FWD Primer GGAAGTGCTTACACACCCATATAL SEQ ID NO: 35 CFH-LP02CFH_FWD Primer CCTGGAAGTGCTTACACACCCATATAL SEQ ID NO: 36 CFH-RP01CFH REV Primer CCAGTGATACATCCAGGTACATTAL SEQ ID NO: 37 CFH-RP02CFH REV Primer ATACATCCAGGTACATTAATCACTCTTAGAACAAL SEQ ID NO: 38 CFH-C01CFH probe for C SNP FAGAGCTQTTAGAATACAGTCCCTGAATGAAAP SEQ ID NO: 39CFH-C04 CFH probe for C SNP FCTTQTAGAATACAGTCCCTGAATGAAAGTTGTAAAGGPSEQ ID NO: 40 CFH-T03 CFH probe for T SNPHAGTTQTTAGAATACAGTCCCTGAATGAAAGTTGTAAP SEQ ID NO: 41 CFH-T04CFH probe for T SNP HTTTQTAGAATACAGTCCCTGAATGAAAGTTGTAAAAGTTAP L =N6-tert-butyl-benzyl dA F = threoninol-FAM Q = BHQ2 P = 3′-Phosphate H =threoninol-HEX S = 7-deaza dG E = CY5.5

Once the genotype of a GA patient was determined using theabove-described TaqMan RT-PCR, it was analyzed for the presence ofparticular risk alleles at the complement loci CFI, C2/CFB and CFH toderive a CFI Profile Status as described in Table 10. CFIProfile+patients were further assessed as likely to respond to treatmentwith anti-Factor D. One selection process is exemplified in Table 10.“+” indicates that the patient is “biomarker-positive” and thus morelikely to respond to anti-factor D therapy; while “−” indicates that thepatient is “biomarker-negative” and thus less likely to respond toanti-factor D therapy. As shown in Table 10, patients having at leastone CFI allele (G) compbined with at least one C2/CFB allele (G) or CFHallele (C on the complimentary strand) are likely responders toanti-factor D therapy. In another instance, patients having at least oneCFI allele (G) are likely responders to anti-factor D therapy. Othersimilar selection criteria may be developed involving these SNPs andSNPs at other complement loci.

TABLE 10 Genotypes at Selected Complement Loci and Definition of CFIProfile Status Genotypes at the complement loci CFH CFI (complementaryProfile CFI C2/CFB strand) Status rs4698775 GG rs429608 GG rs1329428CC + rs4698775 GG rs429608 GG rs1329428 CT + rs4698775 GG rs429608 GGrs1329428 TT + rs4698775 GG rs429608 GA rs1329428 CC + rs4698775 GGrs429608 GA rs1329428 CT + rs4698775 GG rs429608 GA rs1329428 TT +rs4698775 GG rs429608 AA rs1329428 CC + rs4698775 GG rs429608 AArs1329428 CT + rs4698775 GG rs429608 AA rs1329428 TT +/− rs4698775 TGrs429608 GG rs1329428 CC + rs4698775 TG rs429608 GG rs1329428 CT +rs4698775 TG rs429608 GG rs1329428 TT + rs4698775 TG rs429608 GArs1329428 CC + rs4698775 TG rs429608 GA rs1329428 CT + rs4698775 TGrs429608 GA rs1329428 TT + rs4698775 TG rs429608 AA rs1329428 CC +rs4698775 TG rs429608 AA rs1329428 CT + rs4698775 TG rs429608 AArs1329428 TT − rs4698775 TT rs429608 GG rs1329428 CC − rs4698775 TTrs429608 GG rs1329428 CT − rs4698775 TT rs429608 GG rs1329428 TT −rs4698775 TT rs429608 GA rs1329428 CC − rs4698775 TT rs429608 GArs1329428 CT − rs4698775 TT rs429608 GA rs1329428 TT − rs4698775 TTrs429608 AA rs1329428 CC − rs4698775 TT rs429608 AA rs1329428 CT −rs4698775 TT rs429608 AA rs1329428 TT −

Lengthy table referenced here US10093978-20181009-T00001 Please refer tothe end of the specification for access instructions.

Lengthy table referenced here US10093978-20181009-T00002 Please refer tothe end of the specification for access instructions.

Lengthy table referenced here US10093978-20181009-T00003 Please refer tothe end of the specification for access instructions.

Lengthy table referenced here US10093978-20181009-T00004 Please refer tothe end of the specification for access instructions.

LENGTHY TABLES The patent contains a lengthy table section. A copy ofthe table is available in electronic form from the USPTO web site(http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US10093978B2). Anelectronic copy of the table will also be available from the USPTO uponrequest and payment of the fee set forth in 37 CFR 1.19(b)(3).

What is claimed is:
 1. A kit for determining the presence of the degenerative disease-associated polymorphism rs4698775 in the CFI gene and rs1329428 in the CFH gene in a biological sample, comprising reagents and instructions for detecting the genotype of the biological sample for the presence of the degenerative disease-associated polymorphisms rs4698775 in the CFI gene and rs1329428 in the CFH gene, wherein the reagents comprise a set of oligonucleotides having at least 90% identity to and the 3′ terminal nucleotide of SEQ ID NOs: 17, 19, 34, and 36, a set of oligonucleotides having at least 90% identity to SEQ ID NOs: 21 and 38 and a 5′ threoninol-FAM, and a set of oligonucleotides having at least 90% identity to SEO ID NOs: 23 and 40 and a 5′-threoninol-HEX.
 2. The kit according to claim 1, wherein the reagents comprise (i) the forward primer of SEQ ID NO: 17 combined with the reverse primer of SEQ ID NO: 19, the probe of SEQ ID NO: 21 and the probe of SEQ ID NO: 23; and (ii) the forward primer of SEQ ID NO: 34 combined with the reverse primer of SEQ ID NO: 36, the probe of SEQ ID NO: 38 and the probe of SEQ ID NO:
 40. 3. The kit of claim 1 wherein the biological sample is a blood sample, saliva, cheek swab, tissue sample or a sample of bodily fluids.
 4. The kit of claim 1 wherein the biological sample is obtained from a patient diagnosed with a degenerative disease.
 5. The kit of claim 1, wherein the degenerative disease is age related macular degeneration (AMD).
 6. The kit of claim 5, wherein the AMD is early, intermediate or advanced AMD.
 7. The kit of claim 6, wherein the advanced AMD is geographic atrophy (GA). 